Publications by authors named "Hyun-Hee Park"

41 Publications

Telmisartan Inhibits the NLRP3 Inflammasome by Activating the PI3K Pathway in Neural Stem Cells Injured by Oxygen-Glucose Deprivation.

Mol Neurobiol 2021 Apr 6;58(4):1806-1818. Epub 2021 Jan 6.

Department of Neurology, Hanyang University Guri Hospital, 153, Gyeongchun-ro, Guri, 11923, South Korea.

Angiotensin II receptor blockers (ARBs) have been shown to exert neuroprotective effects by suppressing inflammatory and apoptotic responses. In the present study, the effects of the ARB telmisartan on the NLRP3 inflammasome induced by oxygen-glucose deprivation (OGD) in neural stem cells (NSCs) were investigated, as well as their possible association with the activation of the PI3K pathway. Cultured NSCs were treated with different concentrations of telmisartan and subjected to various durations of OGD. Cell counting, lactate dehydrogenase, bromodeoxyuridine, and colony-forming unit assays were performed to measure cell viability and proliferation. In addition, the activity of intracellular signaling pathways associated with the PI3K pathway and NLRP3 inflammasome was evaluated. Telmisartan alone did not affect NSCs up to a concentration of 10 μM under normal conditions but showed toxicity at a concentration of 100 μM. Moreover, OGD reduced the viability of NSCs in a time-dependent manner. Nevertheless, treatment with telmisartan increased the viability and proliferation of OGD-injured NSCs. Furthermore, telmisartan promoted the expression of survival-related proteins and mRNA while inhibiting the expression of death-related proteins induced by OGD. In particular, telmisartan attenuated OGD-dependent expression of the NLRP3 inflammasome and its related signaling proteins. These beneficial effects of telmisartan were blocked by a PI3K inhibitor. Together, these results indicate that telmisartan attenuated the activation of the NLRP3 inflammasome by triggering the PI3K pathway, thereby contributing to neuroprotection.
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http://dx.doi.org/10.1007/s12035-020-02253-1DOI Listing
April 2021

Relationship between telomere shortening and age in Korean individuals with mild cognitive impairment and Alzheimer's disease compared to that in healthy controls.

Aging (Albany NY) 2020 12 15;13(2):2089-2100. Epub 2020 Dec 15.

Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea.

Although telomere length (TL) is highly variable, a shorter TL indicate increased biological age. This multicenter study was conducted to identify the overall correlation between age and TL in Koreans and investigate the associations between age and TL in healthy individuals and patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). TL was measured in peripheral leukocyte DNA. MCI and AD were diagnosed based on clinical examinations and amyloid deposition on positron emission tomography. This study enrolled 437 individuals. Multivariable linear analysis showed an overall approximate TL decrease of 37 bp per 1-year increase in age in all individuals (B=-0.037; P=0.002). There was no significant difference in the mean TL between healthy individuals and individuals with AD. Multivariable linear regression analysis showed that the mean rate of telomere shortening was 60 bp per year in individuals with AD (B=-0.060; P=0.006). There was a negative association between age and TL in our study. Our study results showed more significant telomere shortening per year in women than that in men. In addition, individuals with AD had greater telomere shortening every year than healthy individuals and individuals with MCI.
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http://dx.doi.org/10.18632/aging.202206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880372PMC
December 2020

Development of peptide aptamers as alternatives for antibody in the detection of amyloid-beta 42 aggregates.

Anal Biochem 2020 11 20;609:113921. Epub 2020 Aug 20.

Department of Chemistry and Research Institute of Natural Sciences, Hanyang University, Seoul, 04763, Republic of Korea. Electronic address:

Alzheimer's disease (AD) causes cognitive impairment and serious social isolation. However, there are no effective treatments and even no established confirmatory diagnostic tools for the disease. Amyloid beta (Aβ) aggregation in the brain is the best-known pathognomonic mechanism of AD, so various methods for Aβ detection have been developed for the diagnosis of this disease. We synthesized two novel, ultra-sensitive peptide probes specialized in detecting Aβ aggregates, and examined their potential for future diagnostic application. The peptides are produced through phage high-throughput screening (HTS) and amplified through a serial process called biopanning, which is a repeating method of elution and amplification of probes. We picked phages specific for amyloid from two kinds of phage display. The synthesized peptides were confirmed to have excellent binding affinity to Aβ aggregates, by immunohistochemical staining and western blotting using the brains of 3X transgenic (Tg) AD mice at different stages (5-7, 12-17 months old) of AD severity. In the present study, it was confirmed that newly developed amyloid-binding peptides could be used as novel probes for the detection of Aβ aggregates, which can be used for clinical diagnosis of AD in the future.
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http://dx.doi.org/10.1016/j.ab.2020.113921DOI Listing
November 2020

Micro-RNAs in the aqueous humour of patients with diabetic macular oedema.

Clin Exp Ophthalmol 2020 07 27;48(5):624-635. Epub 2020 Mar 27.

Department of Ophthalmology, Hanyang University College of Medicine, Seoul, Republic of Korea.

Importance: Micro-RNAs (miRNAs) have been studied as new biomarkers or mediators in various diseases, but the value of aqueous humour (AH) miRNAs in diabetic macular oedema (DMO) is still not known.

Background: To compare AH miRNAs and related cytokine expression in DMO patients and healthy controls.

Design: Prospective cross-sectional study.

Participants: Twenty naïve DMO patients and 13 control subjects, who were scheduled for intravitreal injection and cataract surgery, respectively.

Methods: AH samples were collected at the beginning of each procedure and analysed using a miRNA polymerase chain reaction (PCR) array composed of 84 miRNAs, reverse transcripase-quantitative PCR (qPCR) for verifying selected differentially expressed miRNAs, and a cytokine assay, the results of which were compared with bioinformatics conducted to find out genes associated with DMO-related miRNAs.

Main Outcomes Measures: AH expression of miRNAs and cytokines and the bioinformatics results.

Results: Five miRNAs (hsa-miR-185-5p, hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-15b-5p and hsa-miR-15a-5p) showing a fold change greater than -50 in log2 values in the miRNA PCR array were selected, all significantly down-regulated in the DMO group compared to the control group (P < .05), and showed a direct relationship with tumour necrosis factor, nuclear factor kappa B subunit 1 and interleukin-6 (IL-6) in bioinformatics analysis, all of which were related to vascular endothelial growth factor (VEGF). In the cytokine assay, the aqueous concentrations of VEGF, placental growth factor, IL-6 and IL-8 were significantly higher in the DMO group compared to the control group.

Conclusions And Relevance: This study is the first to perform miRNA profiling of the AH of DMO patients. We identified differentially expressed miRNAs in DMO AH, which may be used as potential biomarkers or novel therapeutic targets for DMO.
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http://dx.doi.org/10.1111/ceo.13750DOI Listing
July 2020

Telomere shortening reflecting physical aging is associated with cognitive decline and dementia conversion in mild cognitive impairment due to Alzheimer's disease.

Aging (Albany NY) 2020 03 3;12(5):4407-4423. Epub 2020 Mar 3.

Department of Statistics, Inha University, Incheon 22212, Korea.

We investigated whether telomere length (TL) reflecting physical rather than chronological aging is associated with disease progression in the different cognitive stages of Alzheimer's disease (AD). Study participants included 89 subjects with amyloid pathology (A+), determined through amyloid PET or cerebrospinal fluid analysis, including 26 cognitively unimpaired (CU A+) individuals, 28 subjects with mild cognitive impairment (MCI A+), and 35 subjects with AD dementia (ADD A+). As controls, 104 CU A- individuals were selected. The participants were evaluated annually over two years from baseline. Compared to the highest TL quartile group of MCI A+ participants, the lowest TL quartile group yielded 2-year differences of -9.438 (95% confidence interval [CI] = -14.567 ~ -4.309), -26.708 (-41.576 ~ -11.839), 3.198 (1.323 ~ 5.056), and 2.549 (0.527 ~ 4.571) on the Mini-Mental State Examination, Consortium to Establish a Registry for AD, Clinical Dementia Rating-Sum of Boxes, and Blessed Dementia Scale-Activities of Daily Living, respectively. With this group, the lowest TL quartile group had a significantly greater probability of progressing to ADD than the highest TL quartile group (hazard ratio = 13.16, 95% CI = 1.11 ~ 156.61). Telomere shortening may be associated with rapid cognitive decline and conversion to dementia in MCI A+.
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http://dx.doi.org/10.18632/aging.102893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093181PMC
March 2020

Early increment of soluble triggering receptor expressed on myeloid cells 2 in plasma might be a predictor of poor outcome after ischemic stroke.

J Clin Neurosci 2020 Mar 14;73:215-218. Epub 2020 Feb 14.

Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea; Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Republic of Korea. Electronic address:

Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is derived from cleavage of TREM2, which is expressed on the cell surface of microlgia and other tissue-specific macrophages. In the present study, the changes in the sTREM2 levels after ischemic stroke (IS) and their association with clinical outcomes were evaluated. A total of 43 patients diagnosed with non-cardioembolic IS between June 2011 and May 2014 were consecutively included in this study. Patients treated with intravenous thrombolysis or intra-arterial thrombectomy were excluded. Plasma samples were collected three times (days 1, 7, and 90) after ictus. The sTREM2 level was measured in the samples using the highly sensitive solid-phase proximity ligation assay (SP-PLA). Among the 43 subjects, higher initial NIH stroke scale (NIHSS) score (P = 0.005), early increment of sTREM2 (P < 0.001), and late decrement of sTREM2 (P = 0.002), were more common in patients with poor outcome. Based on multivariate analysis, initial NIHSS score (P = 0.015) and early increment of sTREM2 (P = 0.032) were independently associated with poor outcome. The results from the present study indicate that increment of sTREM2 level at the early phase was a predictor of poor outcome. Serial follow-up of sTREM2 may aid prognosis after stroke.
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http://dx.doi.org/10.1016/j.jocn.2020.02.016DOI Listing
March 2020

LGR5 and Downstream Intracellular Signaling Proteins Play Critical Roles in the Cell Proliferation of Neuroblastoma, Meningioma and Pituitary Adenoma.

Exp Neurobiol 2019 Oct;28(5):628-641

Department of Neurology, Hanyang University Guri Hospital, Guri 11923, Korea.

Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) has been reported to play critical roles in the proliferation of various cancer cells. However, the roles of LGR5 in brain tumors and the specific intracellular signaling proteins directly associated with it remain unknown. Expression of LGR5 was first measured in normal brain tissue, meningioma, and pituitary adenoma of humans. To identify the downstream signaling pathways of LGR5, siRNA-mediated knockdown of was performed in SH-SY5Y neuroblastoma cells followed by proteomics analysis with 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE). In addition, the expression of LGR5-associated proteins was evaluated in LGR5-inhibited neuroblastoma cells and in human normal brain, meningioma, and pituitary adenoma tissue. Proteomics analysis showed 12 protein spots were significantly different in expression level (more than two-fold change) and subsequently identified by peptide mass fingerprinting. A protein association network was constructed from the 12 identified proteins altered by knockdown. Direct and indirect interactions were identified among the 12 proteins. HSP 90-beta was one of the proteins whose expression was altered by knockdown. Likewise, we observed decreased expression of proteins in the hnRNP subfamily following knockdown. In addition, we have for the first time identified significantly higher hnRNP family expression in meningioma and pituitary adenoma compared to normal brain tissue. Taken together, LGR5 and its downstream signaling play critical roles in neuroblastoma and brain tumors such as meningioma and pituitary adenoma.
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http://dx.doi.org/10.5607/en.2019.28.5.628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844835PMC
October 2019

Mitochondria damaged by Oxygen Glucose Deprivation can be Restored through Activation of the PI3K/Akt Pathway and Inhibition of Calcium Influx by Amlodipine Camsylate.

Sci Rep 2019 10 31;9(1):15717. Epub 2019 Oct 31.

Departments of Neurology, Hanyang University Guri Hospital, 11923, Guri, Korea.

Amlodipine, a L-type calcium channel blocker, has been reported to have a neuroprotective effect in brain ischemia. Mitochondrial calcium overload leads to apoptosis of cells in neurologic diseases. We evaluated the neuroprotective effects of amlodipine camsylate (AC) on neural stem cells (NSCs) injured by oxygen glucose deprivation (OGD) with a focus on mitochondrial structure and function. NSCs were isolated from rodent embryonic brains. Effects of AC on cell viability, proliferation, level of free radicals, and expression of intracellular signaling proteins were assessed in OGD-injured NSCs. We also investigated the effect of AC on mitochondrial structure in NSCs under OGD by transmission electron microscopy. AC increased the viability and proliferation of NSCs. This beneficial effect of AC was achieved by strong protection of mitochondria. AC markedly enhanced the expression of mitochondrial biogenesis-related proteins and mitochondrial anti-apoptosis proteins. Together, our results indicate that AC protects OGD-injured NSCs by protecting mitochondrial structure and function. The results of the present study provide insight into the mechanisms underlying the protective effects of AC on NSCs.
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http://dx.doi.org/10.1038/s41598-019-52083-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823474PMC
October 2019

Ultrasensitive Fluorescence Detection of Alzheimer's Disease Based on Polyvalent Directed Peptide Polymer Coupled to a Nanoporous ZnO Nanoplatform.

Anal Chem 2019 05 12;91(9):5573-5581. Epub 2019 Apr 12.

Department of Chemistry and Research Institute for Natural Sciences , Hanyang University , Seoul 04763 , Republic of Korea.

Amyloid-beta 42 (Aβ), the key biomarker of Alzheimer's disease (AD), aggregates to form neurotoxic amyloid plaques. In this work, we modified two fluorescein isothiocyanate-labeled Aβ-targeting peptides and designed an Aβ-specific ultrasensitive polyvalent-directed peptide polymer (PDPP) to enhance AD diagnosis sensitivity. The dissociation constant of Aβ by PDPP was 10-fold higher than the single-site-directed peptide. The improved binding was due to the ability of PDPP to detect multiple receptors on the target. The power of the PDPP diagnostic probe was verified in its application to detect Aβ in cerebrospinal fluid (CSF), which showed a lower limit of detection (LOD) in the fg mL range that is more sensitive than detection by antibodies or single peptides. In addition, we present a novel ultrasensitive diagnostic system using an array of nanoporous ZnO nanoparticles, which play a role in fluorescence signal amplification, to further improve AD diagnosis sensitivity. We enhanced the signal on the basis of the properties of nanoporous ZnO nanoparticles and measured and quantified an ultralow concentration (ag mL range) of Aβ. This PDPP coupled to the nanoporous ZnO-based system is a novel approach to AD diagnosis that might also be useful for the detection of other target biomarkers and clinical applications.
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http://dx.doi.org/10.1021/acs.analchem.8b03735DOI Listing
May 2019

Sublethal Doses of Zinc Protect Rat Neural Stem Cells Against Hypoxia Through Activation of the PI3K Pathway.

Stem Cells Dev 2019 06 22;28(12):769-780. Epub 2019 Apr 22.

1 Department of Neurology, Hanyang University College of Medicine, Seoul, Korea.

Cerebral infarction is one of the major causes of severe morbidity and mortality, and thus, research has focused on developing treatment options for this condition. Zinc (Zn) is an essential element in the central nervous system and has several neuroprotective effects in the brain. In this study, we examined the neuroprotective effects of Zn on neural stem cells (NSCs) exposed to hypoxia. After treatment with several concentrations of Zn, the viability of NSCs under hypoxic conditions was measured by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Trypan blue staining, and a lactate dehydrogenase assay. To evaluate the effect of Zn on the proliferation of NSCs, bromodeoxyuridine/5-bromo-2'-deoxyuridine (BrdU) labeling and colony formation assays were performed. Apoptosis was also examined in NSCs exposed to hypoxia with and without Zn treatment. In addition, a western blot analysis was performed to evaluate the effect of Zn on intracellular signaling proteins. NSC viability and proliferation were decreased under hypoxic conditions, but treatment with sublethal doses of Zn restored viability and proliferation. Sublethal doses of Zn reduced apoptosis caused by hypoxia, increased the expression levels of proteins related to the phosphatidylinositol-3 kinase (PI3K) pathway, and decreased the expression levels of proteins associated with neuronal cell death. These findings confirm that in vivo, sublethal doses of Zn protect NSCs against hypoxia through the activation of the PI3K pathway. Thus, Zn could be employed as a therapeutic option to protect NSCs in ischemic stroke.
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http://dx.doi.org/10.1089/scd.2018.0138DOI Listing
June 2019

Leucine-rich G Protein-coupled Receptor-5 Is Significantly Increased in the Aqueous Humor of Human Eye with Proliferative Diabetic Retinopathy.

Exp Neurobiol 2018 Jun 30;27(3):238-244. Epub 2018 Jun 30.

Department of Ophthalmology, Hanyang University College of Medicine, Seoul 04763, Korea.

Leucine-rich G protein-coupled receptor-5 (LGR5) is known to be a stem cell marker in many organs. LGR5 may have important roles in proliferative diabetic retinopathy (PDR) because LGR5 potentiate the Wnt/β-catenin pathway, which plays crucial roles in pathologic neovascularization in the retina. The association between LGR5 and retinal pathologic neovascularization has not yet been reported. In the present study, LGR5 was compared in human aqueous humor (AH) between normal control and patients with PDR to confirm the relationship between LGR5 and PDR. AH was collected from 7 naïve PDR patients and 3 control subjects before intravitreal injection and cataract surgery, respectively. LGR5 and key members of Wnt/β-catenin were assessed by western blotting. In the present study, it was confirmed for the first time that LGR5 is detected in AH and it increases in PDR patients. Key members of Wnt/β-catenin pathway were also increased in AH of PDR patients compared to control. These findings might support the hypothesis that LGR5 has important roles in PDR especially considering the roles of the Wnt/β-catenin pathway, which is activated by LGR5, contributing to retinal pathologic neovascularization.
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http://dx.doi.org/10.5607/en.2018.27.3.238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050418PMC
June 2018

Differences between the Molecular Mechanisms Underlying Ruptured and Non-Ruptured Carotid Plaques, and the Significance of ABCA1.

J Stroke 2018 Jan 31;20(1):80-91. Epub 2018 Jan 31.

Department of Neurology, Kyung Hee University School of Medicine, Seoul, Korea.

Background And Purpose: Carotid plaques are a strong risk factor for ischemic stroke, and plaque rupture poses an even higher risk. Although many studies have investigated the pathogenic mechanisms of carotid plaque formation, few have studied the differences in molecular mechanisms underlying the rupture and non-rupture of carotid plaques. In addition, since early diagnosis and treatment of carotid plaque rupture are critical for the prevention of ischemic stroke, many studies have sought to identify the important target molecules involved in the rupture. However, a target molecule critical in symptomatic ruptured plaques is yet to be identified.

Methods: A total of 79 carotid plaques were consecutively collected, and microscopically divided into ruptured and non-ruptured groups. Quantitative polymerase chain reaction array, proteomics, and immunohistochemistry were performed to compare the differences in molecular mechanisms between ruptured and non-ruptured plaques. Enzyme-linked immunosorbent assay was used to measure the differences in ATP-binding cassette subfamily A member 1 (ABCA1) levels in the serum.

Results: The expression of several mRNAs and proteins, including ABCA1, was higher in ruptured plaques than non-ruptured plaques. In contrast, the expression of other proteins, including β-actin, was lower in ruptured plaques than non-ruptured plaques. The increased expression of ABCA1 was consistent across several experiments, ABCA1 was positive only in the serum of patients with symptomatic ruptured plaques.

Conclusions: This study introduces a plausible molecular mechanism underlying carotid plaque rupture, suggesting that ABCA1 plays a role in symptomatic rupture. Further study of ABCA1 is needed to confirm this hypothesis.
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http://dx.doi.org/10.5853/jos.2017.02390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836578PMC
January 2018

Neural Stem Cell Death Mechanisms Induced by Amyloid Beta.

Dement Neurocogn Disord 2017 Dec 31;16(4):121-127. Epub 2017 Dec 31.

Department of Neurology, Hanyang University Guri Hospital, Guri, Korea.

Background And Purpose: Amyloid beta (Aβ) is the main component of amyloid plaques, which are deposited in the brains of patients with Alzheimer's disease (AD). Biochemical and animal studies support the central role of Aβ in AD pathogenesis. Despite several investigations focused on the pathogenic mechanisms of Aβ, it is still unclear how Aβ accumulates in the central nervous system and subsequently initiates the disease at the cellular level. In this study, we investigated the pathogenic mechanisms of Aβ using proteomics and antibody microarrays.

Methods: To evaluate the effect of Aβ on neural stem cells (NSCs), we treated primary cultured cortical NSCs with several doses of Aβ for 48 h. A 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, trypan blue staining, and bromodeoxyuridine cell proliferation assay were performed. We detected several intracellular proteins that may be associated with Aβ by proteomics and Western blotting analysis.

Results: Various viability tests showed that Aβ decreased NSCs viability and cell proliferation in a concentration-dependent manner. Aβ treatment significantly decreased lactate dehydrogenase B, high-mobility group box 1, aldolase C, Ezrin, and survival signals including phosphorylated phosphoinositide 3-kinase, Akt, and glycogen synthase kinase-3β.

Conclusions: These results suggest that several factors determined by proteomics and Western blot hold the clue to Aβ pathogenesis. Further studies are required to investigate the role of these factors.
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http://dx.doi.org/10.12779/dnd.2017.16.4.121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428004PMC
December 2017

Tracking and protection of transplanted stem cells using a ferrocenecarboxylic acid-conjugated peptide that mimics hTERT.

Biomaterials 2018 Feb 14;155:80-91. Epub 2017 Nov 14.

Department of Neurology, Hanyang University Guri Hospital, 153, Gyeongchun-ro, Guri-si, Gyeonggi-do 11923, South Korea; Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, 04763, South Korea. Electronic address:

In vivo tracking of transplanted stem cells has been a central aim of stem cell therapy. Although many tracking systems have been introduced, no method has yet been validated for clinical applications. We developed a novel sophisticated peptide (GV1001) that mimics hTERT (human telomerase reverse transcriptase) and analysed its ability to track and protect stem cells after transplantation. Ferrocenecarboxylic acid-conjugated GV1001 (Fe-GV1001) efficiently penetrated stem cells with no adverse effects. Moreover, Fe-GV1001 improved the viability, proliferation, and migration of stem cells under hypoxia. After Fe-GV1001-labelled stem cells were transplanted into the brains of rats after stroke, the labelled cells were easily tracked by MRI. Our findings indicate that Fe-GV1001 can be used for the in vivo tracking of stem cells after transplantation into the brain and can improve the efficacy of stem cell therapy by sustaining and enhancing stem cell characteristics under disease conditions.
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http://dx.doi.org/10.1016/j.biomaterials.2017.11.009DOI Listing
February 2018

Effects of aspirin and clopidogrel on neural stem cells.

Cell Biol Toxicol 2018 06 30;34(3):219-232. Epub 2017 Sep 30.

Department of Neurology, Hanyang University College of Medicine, 153 Gyeongchun-ro, Guri-Si, Gyeonggi-do, Seoul, 11923, South Korea.

Cerebral infarction causes severe morbidity and mortality. Most patients with cerebral infarction should take antiplatelet drugs daily, so the effects of those drugs on the regeneration of the brain need to be investigated. Aspirin and clopidogrel are the most widely used antiplatelet drugs for the prevention of ischemic stroke. We investigated the effects of aspirin and clopidogrel on neural stem cells (NSCs). NSCs were dissociated from fetal rat cortex and cultured with basic fibroblast growth factor and N2 medium. To measure the effects of aspirin and clopidogrel on NSCs, NSCs were treated with several concentrations of aspirin, clopidogrel bisulfate, and clopidogrel resinate for 24 h. After the treatment, we measured cell viability by cell counting kit-8, MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, trypan blue staining, flow cytometry, and lactate dehydrogenase assay. To evaluate their effects on NSC proliferation, we performed BrdU cell proliferation assay and colony-forming unit assay. We compared the intracellular protein level in the NSCs treated with aspirin and two types of clopidogrel, by proteomics analysis. Various viability tests showed that clopidogrel resinate and clopidogrel bisulfate did not affect the viability and proliferation of NSCs whereas aspirin decreased them even at low concentrations which are clinically relevant. Moreover, through the proteomics, it was confirmed that the toxicity of aspirin to NSCs might be associated with the alteration of several intracellular proteins. Taken together, these results suggest that clopidogrel resinate and clopidogrel bisulfate are safe but aspirin could be toxic to NSCs. Therefore, when these antiplatelet agents are prescribed over the long-term, the finding that aspirin could be toxic to NSCs should be considered.
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http://dx.doi.org/10.1007/s10565-017-9412-yDOI Listing
June 2018

Time series analysis of patients seeking orthodontic treatment at Seoul National University Dental Hospital over the past decade.

Korean J Orthod 2017 Sep 27;47(5):298-305. Epub 2017 Jul 27.

Department of Orthodontics, Seoul National University School of Dentistry and Dental Research Institute, Seoul, Korea.

Objective: This paper describes changes in the characteristics of patients seeking orthodontic treatment over the past decade and the treatment they received, to identify any seasonal variations or trends.

Methods: This single-center retrospective cohort study included all patients who presented to Seoul National University Dental Hospital for orthodontic diagnosis and treatment between January 1, 2005 and December 31, 2015. The study analyzed a set of heterogeneous variables grouped into the following categories: demographic (age, gender, and address), clinical (Angle Classification, anomaly, mode of orthodontic treatment, removable appliances for Phase 1 treatment, fixed appliances for Phase 2 treatment, orthognathic surgery, extraction, mini-plate, mini-implant, and patient transfer) and time-related variables (date of first visit and orthodontic treatment time). Time series analysis was applied to each variable.

Results: The sample included 14,510 patients with a median age of 19.5 years. The number of patients and their ages demonstrated a clear seasonal variation, which peaked in the summer and winter. Increasing trends were observed for the proportion of male patients, use of non-extraction treatment modality, use of ceramic brackets, patients from provinces outside the Seoul region at large, patients transferred from private practitioners, and patients who underwent orthognathic surgery performed by university surgeons. Decreasing trends included the use of metal brackets and orthodontic treatment time.

Conclusions: Time series analysis revealed a seasonal variation in some characteristics, and several variables showed changing trends over the past decade.
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http://dx.doi.org/10.4041/kjod.2017.47.5.298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548710PMC
September 2017

Modern trends in Class III orthognathic treatment: A time series analysis.

Angle Orthod 2017 Mar 11;87(2):269-278. Epub 2016 Aug 11.

Objective: To examine the current trends in surgical-orthodontic treatment for patients with Class III malocclusion using time-series analysis.

Materials And Methods: The records of 2994 consecutive patients who underwent orthognathic surgery from January 1, 2004, through December 31, 2015, at Seoul National University Dental Hospital, Seoul, Korea, were reviewed. Clinical data from each surgical and orthodontic treatment record included patient's sex, age at the time of surgery, malocclusion classification, type of orthognathic surgical procedure, place where the orthodontic treatment was performed, orthodontic treatment modality, and time elapsed for pre- and postoperative orthodontic treatment.

Results: Out of the orthognathic surgery patients, 86% had Class III malocclusion. Among them, two-jaw surgeries have become by far the most common orthognathic surgical treatment these days. The age at the time of surgery and the number of new patients had seasonal variations, which demonstrated opposing patterns. There was neither positive nor negative correlation between pre- and postoperative orthodontic treatment time. Elapsed orthodontic treatment time for both before and after Class III orthognathic surgeries has been decreasing over the years.

Conclusion: Results of the time series analysis might provide clinicians with some insights into current surgical and orthodontic management.
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http://dx.doi.org/10.2319/043016-349.1DOI Listing
March 2017

Neural stem cells injured by oxidative stress can be rejuvenated by GV1001, a novel peptide, through scavenging free radicals and enhancing survival signals.

Neurotoxicology 2016 07 2;55:131-141. Epub 2016 Jun 2.

Department of Neurology, Hanyang University College of Medicine, Seoul, South Korea; Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, South Korea. Electronic address:

Oxidative stress is a well-known pathogenic mechanism of a diverse array of neurological diseases, and thus, numerous studies have attempted to identify antioxidants that prevent neuronal cell death. GV1001 is a 16-amino-acid peptide derived from human telomerase reverse transcriptase (hTERT). Considering that hTERT has a strong antioxidant effect, whether GV1001 also has an antioxidant effect is a question of interest. In the present study, we aimed to investigate the effects of GV1001 against oxidative stress in neural stem cells (NSCs). Primary culture NSCs were treated with different concentrations of GV1001 and/or hydrogen peroxide (H2O2) for various time durations. The H2O2 decreased the viability of the NSCs in a concentration-dependent manner, with 200μM H2O2 significantly decreasing both proliferation and migration. However, treatment with GV1001 rescued the viability, proliferation and migration of H2O2-injured NSCs. Consistently, free radical levels were increased in rat NSCs treated with H2O2, while co-treatment with GV1001 significantly reduced these levels, especially the intracellular levels. In addition, GV1001 restored the expression of survival-related proteins and reduced the expression of death-associated ones in NSCs treated with H2O2. In conclusion, GV1001 has antioxidant and neuroprotective effects in NSCs following treatment with H2O2, which appear to be mediated by scavenging free radicals, increasing survival signals and decreasing death signals.
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http://dx.doi.org/10.1016/j.neuro.2016.05.022DOI Listing
July 2016

Neurogenesis in Stroke Recovery.

Transl Stroke Res 2017 02 18;8(1):3-13. Epub 2016 Mar 18.

Department of Neurology, Hanyang University College of Medicine, 249-1 Guri Hospital, Gyomun-dong, Guri-si, Gyeonggi-do, 471-701, Republic of Korea.

Stroke, resulting from limited blood flow to the brain, is one of the most important causes of morbidity and mortality worldwide. Stroke is classified as ischemic, due to lack of blood flow, or hemorrhagic, due to bleeding. Because 87 % of strokes are classified as ischemic, this type will be the predominant focus of this review. Except for thrombolytic therapy, there is no established treatment to reduce the neurological deficits caused by ischemic stroke. Therefore, it is necessary to develop new therapeutic strategies designed to improve neurological functions after ischemic stroke. Recently, therapies to enhance neurogenesis after ischemic stroke have been investigated. However, these approaches have not led to successful clinical outcomes. This review addresses the pathophysiology of stroke, neurogenesis after stroke, and how to stimulate these processes based on the current literature. Finally, ongoing clinical trials to improve neurological functions after stroke by enhancing neurogenesis are discussed in this review.
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http://dx.doi.org/10.1007/s12975-016-0460-zDOI Listing
February 2017

Neuroprotective Effects of Acetyl-L-Carnitine Against Oxygen-Glucose Deprivation-Induced Neural Stem Cell Death.

Mol Neurobiol 2016 12 8;53(10):6644-6652. Epub 2015 Dec 8.

Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Republic of Korea.

Deprivation of oxygen and glucose is the main cause of neuronal cell death during cerebral infarction and can result in severe morbidity and mortality. In general, the neuroprotective therapies that are applied after ischemic stroke have been unsuccessful, despite many investigations. Acetyl-L-carnitine (ALCAR) plays an important role in mitochondrial metabolism and in modulating the coenzyme A (CoA)/acyl-CoA ratio. We investigated the protective effects of ALCAR against oxygen-glucose deprivation (OGD) in neural stem cells (NSCs). We measured cell viability, proliferation, apoptosis, and intracellular signaling protein levels after treatment with varying concentrations of ALCAR under OGD for 8 h. ALCAR protected NSCs against OGD by reducing apoptosis and restoring proliferation. Its protective effects are associated with increases in the expression of survival-related proteins, such as phosphorylated Akt (pAkt), phosphorylated glycogen synthase kinase 3b (pGSK3b), B cell lymphoma 2 (Bcl-2), and Ki-67 in NSCs that were injured by OGD. ALCAR also reduced the expression of death-related proteins, such as Bax, cytosolic cytochrome C, cleaved caspase-9, and cleaved caspase-3. We concluded that ALCAR exhibits neuroprotective effects against OGD-induced damage to NSCs by enhancing the expression of survival signals and decreasing that of death signals.
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http://dx.doi.org/10.1007/s12035-015-9563-xDOI Listing
December 2016

Activation of the phosphatidylinositol 3-kinase pathway plays important roles in reduction of cerebral infarction by cilnidipine.

J Neurochem 2015 Oct 31;135(1):186-93. Epub 2015 Aug 31.

Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Korea.

Cerebral infarction causes permanent neuronal loss inducing severe morbidity and mortality. Because hypertension is the main risk factor for cerebral infarction and most patients with hypertension take antihypertensive drugs daily, the neuroprotective effects and mechanisms of anti-hypertensive drugs need to be investigated. Cilnidipine, a long-acting, new generation 1,4-dihydropyridine inhibitor of both L- and N-type calcium channels, was reported to reduce oxidative stress. In this study, we investigated whether cilnidipine has therapeutic effects in an animal model of cerebral infarction. After determination of the most effective dose of cilnidipine, a total of 128 rats were subjected to middle cerebral artery occlusion. Neurobehavioral function test and brain MRI were performed, and rats with similar sized infarcts were randomized to either the cilnidipine group or the control group. Cilnidipine treatment was performed with reperfusion after 2-h occlusion. Western blots and immunohistochemistry were also performed after 24-h occlusion. Initial infarct volume on diffusion-weighted MRI was not different between the cilnidipine group and the control group; however, fluid-attenuated inversion recovery MRI at 24 h showed significantly reduced infarct volume in the cilnidipine group compared with the control group. Cilnidipine treatment significantly decreased the number of triphosphate nick end labeling-positive cells compared to the control group. Western blot and immunohistochemistry showed increased expression of phosphorylated Akt (Ser473), phosphorylated glycogen synthase kinase-3β, and Bcl-2 and decreased expression of Bax and cleaved caspase-3. These results suggest that cilnidipine, which is used for the treatment of hypertension, has neuroprotective effects in the ischemic brain through activation of the PI3K pathway. We investigated whether cilnidipine has neuroprotective effects on ischemic stroke in an animal model. We have demonstrated that the neuroprotective effect of cilnidipine is associated with the activation of the PI3K pathway. Considering the daily use of antihypertensive drugs for patients with hypertension, cilnidipine could be beneficial for patients with ischemic stroke.
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http://dx.doi.org/10.1111/jnc.13254DOI Listing
October 2015

Increased VEGF and decreased SDF-1α in patients with silent brain infarction are associated with better prognosis after first-ever acute lacunar stroke.

J Stroke Cerebrovasc Dis 2015 Mar 16;24(3):704-10. Epub 2015 Jan 16.

Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea; Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science and Engineering, Seoul, Republic of Korea. Electronic address:

Background: Pre-existing silent brain infarctions (SBIs) have been reported to be associated with better outcomes after first-ever symptomatic ischemic stroke, although the mechanism of this remains unclear. We investigated the association between SBIs, outcomes of acute lacunar infarction, and biomarkers including vascular endothelial growth factor (VEGF), stromal cell-derived factor-1α (SDF-1α), macrophage migration inhibitory factor (MIF), and high-mobility group box-1 (HMGB1).

Methods: A total of 68 consecutive patients diagnosed with first-ever lacunar infarction (<20 mm) within 24 hours of symptom onset were included in this study. Clinical, laboratory, and imaging data were obtained. Plasma levels of VEGF, SDF-1α, MIF, and HMGB1 were assessed using Enzyme-Linked Immunosorbent Assay kits.

Results: SBIs were noted in 31 of the 68 patients. Although the initial National Institutes of Health Stroke Scale scores were not related with the presence of SBIs (P = .313), patients with SBIs had better outcomes at 3 months (P = .029). Additionally, plasma VEGF levels were higher (P = .035) and SDF-1α levels were lower (P < .001) in patients with SBIs. Logistic regression analysis indicated that VEGF and SDF-1α were independently associated with the presence of SBIs.

Conclusions: SBIs are associated with favorable outcomes in patients with first-ever acute lacunar infarction and higher levels of VEGF, and lower levels of SDF-1α in these patients may contribute to their more favorable prognosis.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.11.021DOI Listing
March 2015

1,25-dyhydroxyvitamin D3 attenuates L-DOPA-induced neurotoxicity in neural stem cells.

Mol Neurobiol 2015 Apr 8;51(2):558-70. Epub 2014 Aug 8.

Department of Neurology, Hanyang University College of Medicine, Seoul, South Korea.

The neurotoxicity of levodopa (L-DOPA) on neural stem cells (NSCs) and treatment strategies to protect NSCs from this neurotoxicity remain to be elucidated. Recently, an active form of vitamin D3 has been reported to display neuroprotective properties. Therefore, we investigated the protective effect of 1,25-dyhydroxyvitamin D3 (calcitriol) on L-DOPA-induced NSC injury. We measured cell viability via the cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays and Annexin V/PI staining followed by flow cytometry, cell proliferation using the BrdU and colony-forming unit (CFU) assays, cell differentiation via immunocytochemistry, the levels of free radicals via 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining, apoptosis via DAPI and TUNEL staining, and intracellular signaling protein expression via Western blot. Antibody microarrays were also employed to detect changes in the expression of prosurvival- and death-related proteins. Treatment of NSCs with L-DOPA reduced their viability and proliferation. This treatment also increased the levels of free radicals and decreased the expression levels of intracellular signaling proteins that are associated with cell survival. However, simultaneous exposure to calcitriol significantly reduced these effects. The calcitriol-mediated protection against L-DOPA toxicity was blocked by the phosphoinositide 3-kinase (PI3K) inhibitor LY294004. L-DOPA also inhibited the expression of Nestin and Ki-67, and co-treatment with calcitriol alleviated these effects. The expression levels of GFAP, DCX, and Tuj1 were not significantly affected by treatment with L-DOPA or calcitriol. Calcitriol protects against L-DOPA-induced NSC injury by promoting prosurvival signaling, including activation of the PI3K pathway, and reducing oxidative stress.
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http://dx.doi.org/10.1007/s12035-014-8835-1DOI Listing
April 2015

Analysis of variation in total airborne bacteria concentration to assess the performance of biological safety cabinets in microbial laboratories.

Saf Health Work 2014 Mar 24;5(1):23-6. Epub 2014 Jan 24.

Institute of Health and Environment, School of Public Health, Seoul National University, Seoul, Korea.

Background: The purpose of this study was to compare the concentration of total airborne bacteria (TAB) in biosafety cabinets (BSCs) at universities and hospital microbial laboratories to assess the performance of BSCs.

Methods: TAB was determined by using the single-stage Anderson sampler (BioStage Viable Cascade Impactor). The samples were obtained three times (with the BSC turned off and the shield open; with the BSC turned off and the shield closed; and with the BSC tuned on and operating) from the areas in front of 11 BSCs.

Results: TAB concentrations of accredited and nonaccredited BSCs were determined. No significant differences were observed in the TAB concentrations of the accredited BSCs and the nonaccredited BSCs for the areas outside the BSCs in the laboratories (p > 0.05). TAB concentrations for the BSCs sampled with the shield open and the instrument turned off showed differences based on the sampling site outside the BSC in each laboratory.

Conclusion: These results imply that TAB concentration is not altered by the performance of the BSCs or TAB itself and/or concentration of TAB outside the BSC is not a good index of BSC performance.
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http://dx.doi.org/10.1016/j.shaw.2014.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048000PMC
March 2014

Neuroprotective effects of amlodipine besylate and benidipine hydrochloride on oxidative stress-injured neural stem cells.

Brain Res 2014 Mar 16;1551:1-12. Epub 2014 Jan 16.

Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea; Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Republic of Korea. Electronic address:

Hypertension is associated with oxidative stress. Amlodipine besylate (AB) and benidipine hydrochloride (BH), which are Ca(2+) antagonists, have been reported to reduce oxidative stress. In this study, we examined the neuroprotective effects of AB and BH on oxidative stress-injured neural stem cells (NSCs), with a focus on the phosphatidylinositol 3-kinase (PI3K) pathway and the extracellular signal-regulated kinase (ERK) pathway. After treatment with H2O2, the viability of NSCs decreased in a concentration-dependent manner; however, co-treatment with AB or BH restored the viability of H2O2-injured NSCs. H2O2 increased free radical production and apoptosis in NSCs, whereas co-treatment with AB or BH attenuated these effects. To evaluate the effects of AB or BH on the H2O2-inhibited proliferation of NSCs, we performed BrdU labeling and colony formation assays and found that NSC proliferation decreased upon H2O2 treatment but that combined treatment with AB or BH restored this proliferation. Western blot analysis showed that AB and BH increased the expression of cell survival-related proteins that were linked with the PI3K and ERK pathways but decreased the expression of cell death-related proteins. To investigate whether the PI3K and ERK pathways were directly involved in the neuroprotective effects of AB and BH on H2O2-treated NSCs, NSCs were pretreated with the PI3K inhibitor, LY294002, or the ERK inhibitor, FR180204, which significantly blocked the effects of AB and BH. Together, our results suggest that AB and BH restore the H2O2-inhibited viability and proliferation of NSCs by inhibiting oxidative stress and by activating the PI3K and ERK pathways.
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http://dx.doi.org/10.1016/j.brainres.2014.01.016DOI Listing
March 2014

Novel vaccine peptide GV1001 effectively blocks β-amyloid toxicity by mimicking the extra-telomeric functions of human telomerase reverse transcriptase.

Neurobiol Aging 2014 Jun 26;35(6):1255-74. Epub 2013 Dec 26.

Department of Neurology, Hanyang University College of Medicine, Guri, Gyeonggi, Korea; Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Korea. Electronic address:

GV1001 is a 16-amino-acid vaccine peptide derived from the human telomerase reverse transcriptase sequence. We investigated the effects of GV1001 against β-amyloid (Aβ) oligomer-induced neurotoxicity in rat neural stem cells (NSCs). Primary culture NSCs were treated with several concentrations of GV1001 and/or Aβ₂₅₋₃₅ oligomer for 48 hours. GV1001 protected NSCs against the Aβ₂₅₋₃₅ oligomer in a concentration-dependent manner. Aβ₂₅₋₃₅ concentration dependently decreased viability, proliferation, and mobilization of NSCs and GV1001 treatment restored the cells to wild-type levels. Aβ₂₅₋₃₅ increased free radical levels in rat NSCs while combined treatment with GV1001 significantly reduced these levels. In addition, GV1001 treatment of Aβ₂₅₋₃₅-injured NSCs increased the expression level of survival-related proteins, including mitochondria-associated survival proteins, and decreased the levels of death and inflammation-related proteins, including mitochondria-associated death proteins. Together, these results suggest that GV1001 possesses neuroprotective effects against Aβ₂₅₋₃₅ oligomer in NSCs and that these effects are mediated through mimicking the extra-telomeric functions of human telomerase reverse transcriptase, including the induction of cellular proliferation, anti-apoptotic effects, mitochondrial stabilization, and anti-aging and anti-oxidant effects.
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http://dx.doi.org/10.1016/j.neurobiolaging.2013.12.015DOI Listing
June 2014

Coenzyme Q10 restores amyloid beta-inhibited proliferation of neural stem cells by activating the PI3K pathway.

Stem Cells Dev 2013 Aug 10;22(15):2112-20. Epub 2013 Apr 10.

Department of Neurology, Hanyang University College of Medicine, Seoul, Korea.

Neurogenesis in the adult brain is important for memory and learning, and the alterations in neural stem cells (NSCs) may be an important part of Alzheimer's disease pathogenesis. The phosphatidylinositol 3-kinase (PI3K) pathway has been suggested to play an important role in neuronal cell survival and is highly involved in adult neurogenesis. Recently, coenzyme Q10 (CoQ10) was found to affect the PI3K pathway. We investigated whether CoQ10 could restore amyloid β (Aβ)25-35 oligomer-inhibited proliferation of NSCs by focusing on the PI3K pathway. To evaluate the effects of CoQ10 on Aβ25-35 oligomer-inhibited proliferation of NSCs, NSCs were treated with several concentrations of CoQ10 and/or Aβ25-35 oligomers. BrdU labeling, Colony Formation Assays, and immunoreactivity of Ki-67, a marker of proliferative activity, showed that NSC proliferation decreased with Aβ25-35 oligomer treatment, but combined treatment with CoQ10 restored it. Western blotting showed that CoQ10 treatment increased the expression levels of p85α PI3K, phosphorylated Akt (Ser473), phosphorylated glycogen synthase kinase-3β (Ser9), and heat shock transcription factor, which are proteins related to the PI3K pathway in Aβ25-35 oligomers-treated NSCs. To confirm a direct role for the PI3K pathway in CoQ10-induced restoration of proliferation of NSCs inhibited by Aβ25-35 oligomers, NSCs were pretreated with a PI3K inhibitor, LY294002; the effects of CoQ10 on the proliferation of NSCs inhibited by Aβ25-35 oligomers were almost completely blocked. Together, these results suggest that CoQ10 restores Aβ25-35 oligomer-inhibited proliferation of NSCs by activating the PI3K pathway.
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http://dx.doi.org/10.1089/scd.2012.0604DOI Listing
August 2013

Coenzyme Q10 protects neural stem cells against hypoxia by enhancing survival signals.

Brain Res 2012 Oct 21;1478:64-73. Epub 2012 Aug 21.

Department of Neurology, Hanyang University College of Medicine, Seoul, Korea.

Recanalization and secondary prevention are the main therapeutic strategies for acute ischemic stroke. Neuroprotective therapies have also been investigated despite unsuccessful clinical results. Coenzyme Q10 (CoQ10), which is an essential cofactor for electron transport in mitochondria, is known to have an antioxidant effect. We investigated the protective effects of CoQ10 against hypoxia in neural stem cells (NSCs). We measured cell viability and levels of intracellular signaling proteins after treatment with several concentrations of CoQ10 under hypoxia-reperfusion. CoQ10 protected NSCs against hypoxia-reperfusion in a concentration-dependent manner by reducing growth inhibition and inhibiting free radical formation. It increased the expression of a number of survival-related proteins such as phosphorylated Akt (pAkt), phosphorylated glycogen synthase kinase 3-β (pGSK3-β), and B-cell lymphoma 2 (Bcl-2) in NSCs injured by hypoxia-reperfusion and reduced the expression of death-related proteins such as cleaved caspase-3. We conclude that CoQ10 has effects against hypoxia-reperfusion induced damage to NSCs by enhancing survival signals and decreasing death signals.
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http://dx.doi.org/10.1016/j.brainres.2012.08.025DOI Listing
October 2012

Exposure to Volatile Organic Compounds and Possibility of Exposure to By-product Volatile Organic Compounds in Photolithography Processes in Semiconductor Manufacturing Factories.

Saf Health Work 2011 Sep 30;2(3):210-7. Epub 2011 Sep 30.

Occupational Safety and Health Research Institute, Korea Occupational Safety and Health Agency, Incheon, Korea.

Objectives: The purpose of this study was to measure the concentration of volatile organic compound (VOC)s originated from the chemicals used and/or derived from the original parental chemicals in the photolithography processes of semiconductor manufacturing factories.

Methods: A total of four photolithography processes in 4 Fabs at three different semiconductor manufacturing factories in Korea were selected for this study. This study investigated the types of chemicals used and generated during the photolithography process of each Fab, and the concentration levels of VOCs for each Fab.

Results: A variety of organic compounds such as ketone, alcohol, and acetate compounds as well as aromatic compounds were used as solvents and developing agents in the processes. Also, the generation of by-products, such as toluene and phenol, was identified through a thermal decomposition experiment performed on a photoresist. The VOC concentration levels in the processes were lower than 5% of the threshold limit value (TLV)s. However, the air contaminated with chemical substances generated during the processes was re-circulated through the ventilation system, thereby affecting the airborne VOC concentrations in the photolithography processes.

Conclusion: Tens of organic compounds were being used in the photolithography processes, though the types of chemical used varied with the factory. Also, by-products, such as aromatic compounds, could be generated during photoresist patterning by exposure to light. Although the airborne VOC concentrations resulting from the processes were lower than 5% of the TLVs, employees still could be exposed directly or indirectly to various types of VOCs.
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http://dx.doi.org/10.5491/SHAW.2011.2.3.210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430900PMC
September 2011