Lee JY

References (39)

Title : The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism - Oh_2023_Nat.Commun_14_5728
Author(s) : Oh M , Jang SY , Lee JY , Kim JW , Jung Y , Kim J , Seo J , Han TS , Jang E , Son HY , Kim D , Kim MW , Park JS , Song KH , Oh KJ , Kim WK , Bae KH , Huh YM , Kim SH , Han BS , Lee SC , Hwang GS , Lee EW
Ref : Nat Commun , 14 :5728 , 2023
Abstract : Arachidonic and adrenic acids in the membrane play key roles in ferroptosis. Here, we reveal that lipoprotein-associated phospholipase A2 (Lp-PLA2) controls intracellular phospholipid metabolism and contributes to ferroptosis resistance. A metabolic drug screen reveals that darapladib, an inhibitor of Lp-PLA2, synergistically induces ferroptosis in the presence of GPX4 inhibitors. We show that darapladib is able to enhance ferroptosis under lipoprotein-deficient or serum-free conditions. Furthermore, we find that Lp-PLA2 is located in the membrane and cytoplasm and suppresses ferroptosis, suggesting a critical role for intracellular Lp-PLA2. Lipidomic analyses show that darapladib treatment or deletion of PLA2G7, which encodes Lp-PLA2, generally enriches phosphatidylethanolamine species and reduces lysophosphatidylethanolamine species. Moreover, combination treatment of darapladib with the GPX4 inhibitor PACMA31 efficiently inhibits tumour growth in a xenograft model. Our study suggests that inhibition of Lp-PLA2 is a potential therapeutic strategy to enhance ferroptosis in cancer treatment.
ESTHER : Oh_2023_Nat.Commun_14_5728
PubMedSearch : Oh_2023_Nat.Commun_14_5728
PubMedID: 37714840

Title : Discovery of (E)-2-(Hydroxyimino)-N-(2 ((4methylpentyl)amino)ethyl)acetamide (KR-27425) as a non-pyridinium oxime reactivator of paraoxon-inhibited acetylcholinesterase - Vishakantegowda_2023_Bioorg.Med.Chem.Lett__129504
Author(s) : Vishakantegowda AG , Solomon Girmay B , Soo Shin J , Lee JY , Ahn S , Jung YS
Ref : Bioorganic & Medicinal Chemistry Lett , :129504 , 2023
Abstract : This study aimed to explore non-pyridinium oxime acetylcholinesterase (AChE) reactivators that could hold the potential to overcome the limitations of the currently available compounds used in the clinic to treat the neurologic manifestations induced by intoxication with organophosphorus agents. Fifteen compounds with various non-pyridinium oxime moieties were evaluated for AChE activity at different concentrations, including aldoximes, ketoximes, and alpha-ketoaldoximes. The therapeutic potential of the oxime compounds was evaluated by assessing their ability to reactivate AChE inhibited by paraoxon. Among the tested compounds, alpha-Ketoaldoxime derivative 13 showed the highest reactivation (%) reaching 67% and 60% AChE reactivation when evaluated against OP-inhibited electric eel AChE at concentrations of 1,000 and 100 microM, respectively. Compound 13 showed a comparable reactivation ability of AChE (60%) compared to that of pralidoxime (56%) at concentrations of 100 microM. Molecular docking simulation of the most active compounds 12 and 13 was conducted to predict the binding mode of the reactivation of electric eel AChE. As a result, a non-pyridinium oxime moiety 13, is a potential reactivator of OP-inhibited AChE and is taken as a lead compound for the development of novel AChE reactivators with enhanced capacity to freely cross the blood-brain barrier.
ESTHER : Vishakantegowda_2023_Bioorg.Med.Chem.Lett__129504
PubMedSearch : Vishakantegowda_2023_Bioorg.Med.Chem.Lett__129504
PubMedID: 37838342

Title : The effectiveness and safety of Jihwang-eumja (Dihuang Yizi) compared to Western medications in patients with Alzheimer's disease: A systematic review and meta-analysis - Kim_2023_Complement.Ther.Clin.Pract_51_101746
Author(s) : Kim JY , Lee JY , Jung JH , Park YC , Jung IC
Ref : Complement Ther Clin Pract , 51 :101746 , 2023
Abstract : BACKGROUND AND PURPOSE: Jihwang-eumja is reported to be effective in decreasing beta-amyloid expression and activating monoamine oxidase and acetylcholinesterase in rat models. This systematic review aims to evaluate the effectiveness of Jihwang-eumja in Alzheimer's disease compared to Western medications. METHODS: We searched Medline, Embase, CENTRAL, CINAHL, CNKI, ScienceON, KISS, and Kmbase. Randomized controlled trials comparing the effectiveness of Jihwang-eumja and Western medications on the cognition and the activities of daily living in Alzheimer's disease were included. The results were synthesized using meta-analysis. The risk of bias was evaluated using the Cochrane risk-of-bias tool, and the evidence level of each outcome was suggested using the GRADE system. RESULTS: A total of 165 studies were screened, and six were included in the systematic review and meta-analysis. A total of 245 and 240 participants were included in the intervention and comparison groups, respectively. The results showed that Mini-Mental State Examination was 3.19 (95%CI: 1.68-4.70) higher, and the standardized mean difference of activities of daily living was 1.13 (95%CI: 0.89-1.37) higher in the Jihwang-eumja group than in Western medications group. The included studies contained some concerns of the risk of bias, and the certainty of the evidence was considered moderate. CONCLUSION: Despite the small number of studies and high heterogeneity, we could verify the applicability of Jihwang-eumja for Alzheimer's disease.
ESTHER : Kim_2023_Complement.Ther.Clin.Pract_51_101746
PubMedSearch : Kim_2023_Complement.Ther.Clin.Pract_51_101746
PubMedID: 36933451

Title : Optimization of Solid-Phase Extraction of a Degradation Product of Novichok (A234) and Its Application to Environmental Samples - Lee_2023_J.Anal.Toxicol_47_81
Author(s) : Lee JY , Shin JY , Kim HS
Ref : J Anal Toxicol , 47 :81 , 2023
Abstract : There have been no detailed investigations regarding solid-phase-extraction (SPE) optimization and screening for the degradation products of ethyl (1-(diethylamino)ethylidene)phosphoramidofluoridate (A234) in various environmental samples. Therefore, as a first step in the selective SPE of the degradation products of A234, we optimized the SPE adsorption and extraction parameters for the A234 degradation product ethylhydrogen (1-(diethylamino)ethylidene)phosphoramidate (cpd 1). Among various SPE cartridges, the Si cartridge (500 mg, 3 mL) selectively extracted cpd 1 using an elution volume of 4 mL of 25% H2O in acetonitrile, which eliminated most interference without cpd 1 loss during loading and washing. In addition, the sorbent capacity is also critical in the adsorption of cpd 1. The Si cartridge (500 mg, 3 mL) retained cpd 1 in the concentration range 1-10 microg/mL. The linearity of detector response of cpd 1 in deionized H2O was studied in the range of 1.0-100 ng/mL and showed good linearity with gamma2 ranging from 0.9979 to 0.996. The limits of detection for cpd 1 are 10 ng/mL in the product-scan mode and 100 ng/mL in the full-scan mode. Also, after we optimized the SPE method, we validated the precision and accuracy of the Si-cartridge extraction method in real soil samples with diverse concentrations. The precision ranged from 2.5% to 5.3%. This newly developed SPE is applicable to the analysis of a degradation product of Novichok A234 in various environmental matrices, such as water, soil and sand, in the Organization for the Prohibition of Chemical Weapons (OPCW) proficiency test and unknown samples collected from suspected sites.
ESTHER : Lee_2023_J.Anal.Toxicol_47_81
PubMedSearch : Lee_2023_J.Anal.Toxicol_47_81
PubMedID: 35640302

Title : Vapor Pressure and Toxicity Prediction for Novichok Agent Candidates Using Machine Learning Model: Preparation for Unascertained Nerve Agents after Chemical Weapons Convention Schedule 1 Update - Jeong_2022_Chem.Res.Toxicol_35_774
Author(s) : Jeong K , Lee JY , Woo S , Kim D , Jeon Y , Ryu TI , Hwang SR , Jeong WH
Ref : Chemical Research in Toxicology , 35 :774 , 2022
Abstract : The recent terrorist attacks using Novichok agents and subsequent operations have necessitated an understanding of its physicochemical properties, such as vapor pressure and toxicity, as well as unascertained nerve agent structures. To prevent continued threats from new types of nerve agents, the organization for the prohibition of chemical weapons (OPCW) updated the chemical weapons convention (CWC) schedule 1 list. However, this information is vague and may encompass more than 10 000 possible chemical structures, which makes it almost impossible to synthesize and measure their properties and toxicity. To assist this effort, we successfully developed machine learning (ML) models to predict the vapor pressure to help with escape and removal operations. The model shows robust and high-accuracy performance with promising features for predicting vapor pressure when applied to Novichok materials and accurate predictions with reasonable errors. The ML classification model was successfully built for the swallow globally harmonized system class of organophosphorus compounds (OP) for toxicity predictions. The tuned ML model was used to predict the toxicity of Novichok agents, as described in the CWC list. Although its accuracy and linearity can be improved, this ML model is expected to be a firm basis for developing more accurate models for predicting the vapor pressure and toxicity of nerve agents in the future to help handle future terror attacks with unknown nerve agents.
ESTHER : Jeong_2022_Chem.Res.Toxicol_35_774
PubMedSearch : Jeong_2022_Chem.Res.Toxicol_35_774
PubMedID: 35317551

Title : Precisely predicting the (1)H and (13)C NMR chemical shifts in new types of nerve agents and building spectra database - Jeong_2022_Sci.Rep_12_20288
Author(s) : Jeong K , Ryu TI , Hwang SR , Cho Y , Lim KC , Yoon UH , Lee JY , Yoon YW , Jeong HJ
Ref : Sci Rep , 12 :20288 , 2022
Abstract : Following the recent terrorist attacks using Novichok agents and the subsequent decomposition operations, understanding the chemical structures of nerve agents has become important. To mitigate the ever-evolving threat of new variants, the Organization for the Prohibition of Chemical Weapons has updated the list of Schedule 1 substances defined by the Chemical Weapons Convention. However, owing to the several possible structures for each listed substance, obtaining an exhaustive dataset is almost impossible. Therefore, we propose a nuclear magnetic resonance-based prediction method for (1)H and (13)C NMR chemical shifts of Novichok agents based on conformational and density functional study calculations. Four organophosphorus compounds and five G- and V-type nerve agents were used to evaluate the accuracy of the proposed procedure. Moreover, (1)H and (13)C NMR prediction results for an additional 83 Novichok candidates were compiled as a database to aid future research and identification. Further, this is the first study to successfully predict the NMR chemical shifts of Novichok agents, with an exceptional agreement between predicted and experimental data. The conclusions enable the prediction of all possible structures of Novichok agents and can serve as a firm foundation for preparation against future terrorist attacks using new variants of nerve agents.
ESTHER : Jeong_2022_Sci.Rep_12_20288
PubMedSearch : Jeong_2022_Sci.Rep_12_20288
PubMedID: 36434133

Title : Subcutaneously Injectable Hyaluronic Acid Hydrogel for Sustained Release of Donepezil with Reduced Initial Burst Release: Effect of Hybridization of Microstructured Lipid Carriers and Albumin - Kang_2021_Pharmaceutics_13_2
Author(s) : Kang NW , Yoon SY , Kim S , Yu NY , Park JH , Lee JY , Cho HJ , Kim DD
Ref : Pharmaceutics , 13 : , 2021
Abstract : The daily oral administration of acetylcholinesterase (AChE) inhibitors for Alzheimer's disease features low patient compliance and can lead to low efficacy or high toxicity owing to irregular intake. Herein, we developed a subcutaneously injectable hyaluronic acid hydrogel (MLC/HSA hydrogel) hybridized with microstructured lipid carriers (MLCs) and human serum albumin (HSA) for the sustained release of donepezil (DNP) with reduced initial burst release. The lipid carrier was designed to have a microsized mean diameter (32.6 +/- 12.8 microm) to be well-localized in the hydrogel. The hybridization of MLCs and HSA enhanced the structural integrity of the HA hydrogel, as demonstrated by the measurements of storage modulus (G'), loss modulus (G''), and viscosity. In the pharmacokinetic study, subcutaneous administration of MLC/HSA hydrogel in rats prolonged the release of DNP for up to seven days and reduced the initial plasma concentration, where the C(max) value was 0.3-fold lower than that of the control hydrogel without a significant change in the AUC(last) value. Histological analyses of the hydrogels supported their biocompatibility for subcutaneous injection. These results suggest that a new hybrid MLC/HSA hydrogel could be promising as a subcutaneously injectable controlled drug delivery system for the treatment of Alzheimer's disease.
ESTHER : Kang_2021_Pharmaceutics_13_2
PubMedSearch : Kang_2021_Pharmaceutics_13_2
PubMedID: 34208289

Title : Characterization and Study on Fragmentation Pathways of a Novel Nerve Agent, 'Novichok (A234)', in Aqueous Solution by Liquid Chromatography-Tandem Mass Spectrometry - Lee_2021_Molecules_26_
Author(s) : Lee JY , Lim KC , Kim HS
Ref : Molecules , 26 : , 2021
Abstract : As a first step toward studying the properties of Novichok (ethyl (1-(diethylamino)ethylidene)phosphoramidofluoridate (A234)), we investigated its degradation products and fragmentation pathways in aqueous solution at different pH levels by liquid chromatography-tandem mass spectrometry. A234 was synthesized in our laboratory and characterized by nuclear magnetic resonance spectroscopy. Three sets of aqueous samples were prepared at different pH levels. A stock solution of A234 was prepared in acetonitrile at a concentration of 1 mg/mL and stored at -20 degreesC until use. Aqueous samples (0.1 mg/mL) were prepared by diluting the stock solution with deionized water. The acidic aqueous sample (pH = 3.5) and basic aqueous sample (pH = 9.4) were prepared using 0.01 M acetic acid and 0.01 M potassium carbonate, respectively. The analysis of the fragmentation patterns and degradation pathways of A234 showed that the same degradation products were formed at all pH levels. However, the hydrolysis rate of A234 was fastest under acidic conditions. In all three conditions, the fragmentation pattern and the major degradation product of A234 were determined. This information will be applicable to studies regarding the decontamination of Novichok and the trace analysis of its degradation products in various environmental matrices.
ESTHER : Lee_2021_Molecules_26_
PubMedSearch : Lee_2021_Molecules_26_
PubMedID: 33670472

Title : Identification and Study of Biomarkers from Novichok-Inhibited Butyrylcholinesterase in Human Plasma - Jeong_2021_Molecules_26_3810
Author(s) : Jeong WH , Lee JY , Lim KC , Kim HS
Ref : Molecules , 26 : , 2021
Abstract : To identify biomarkers of ethyl (1-(diethylamino)ethylidene)phosphoramidofluoridate (A234)- or methyl (1-(diethylamino)ethylidene)phosphoramidofluoridate (A232)-inhibited butyrylcholinesterase (BChE), we investigated nonapeptide adducts containing the active site serine, which plays a key role in enzyme activity, using LC-MS/HRMS. Biomarkers were acquired as expected, and they exhibited a significant amount of fragment ions from the inhibiting agent itself, in contrast to the MS2 spectra of conventional nerve agents. These biomarkers had a higher abundance of [M+2H](2+) ions than [M+H](+) ions, making doubly charged ions more suitable for trace analysis.
ESTHER : Jeong_2021_Molecules_26_3810
PubMedSearch : Jeong_2021_Molecules_26_3810
PubMedID: 34206601

Title : Inhibition of Butyrylcholinesterase and Human Monoamine Oxidase-B by the Coumarin Glycyrol and Liquiritigenin Isolated from Glycyrrhiza uralensis - Jeong_2020_Molecules_25_
Author(s) : Jeong GS , Kang MG , Lee JY , Lee SR , Park D , Cho M , Kim H
Ref : Molecules , 25 : , 2020
Abstract : Eight compounds were isolated from the roots of Glycyrrhiza uralensis and tested for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activities. The coumarin glycyrol (GC) effectively inhibited butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) with IC(50) values of 7.22 and 14.77 muM, respectively, and also moderately inhibited MAO-B (29.48 muM). Six of the other seven compounds only weakly inhibited AChE and BChE, whereas liquiritin apioside moderately inhibited AChE (IC(50) = 36.68 muM). Liquiritigenin (LG) potently inhibited MAO-B (IC(50) = 0.098 muM) and MAO-A (IC(50) = 0.27 muM), and liquiritin, a glycoside of LG, weakly inhibited MAO-B (>40 muM). GC was a reversible, noncompetitive inhibitor of BChE with a K(i) value of 4.47 muM, and LG was a reversible competitive inhibitor of MAO-B with a K(i) value of 0.024 muM. Docking simulations showed that the binding affinity of GC for BChE (-7.8 kcal/mol) was greater than its affinity for AChE (-7.1 kcal/mol), and suggested that GC interacted with BChE at Thr284 and Val288 by hydrogen bonds (distances: 2.42 and 1.92 , respectively) beyond the ligand binding site of BChE, but that GC did not form hydrogen bond with AChE. The binding affinity of LG for MAO-B (-8.8 kcal/mol) was greater than its affinity for MAO-A (-7.9 kcal/mol). These findings suggest GC and LG should be considered promising compounds for the treatment of Alzheimer's disease with multi-targeting activities.
ESTHER : Jeong_2020_Molecules_25_
PubMedSearch : Jeong_2020_Molecules_25_
PubMedID: 32859055

Title : Effect of anticholinergic burden on treatment modification, delirium and mortality in newly diagnosed dementia patients starting a cholinesterase inhibitor: A population-based study - Ah_2019_Basic.Clin.Pharmacol.Toxicol_124_741
Author(s) : Ah YM , Suh Y , Jun K , Hwang S , Lee JY
Ref : Basic Clin Pharmacol Toxicol , 124 :741 , 2019
Abstract : Few studies have evaluated the association between anticholinergic burden and treatment modification after starting a cholinesterase inhibitor in clinical practice. We aimed to evaluate the effect of anticholinergic burden on anti-dementia treatment modification, delirium and mortality. We retrospectively analysed older adults (n = 25 825) who started a cholinesterase inhibitor during 2003-2011 from Korean National Health Insurance Service Senior Cohort Database. High anticholinergic burden was defined as an average daily Anticholinergic Cognitive Burden (ACB) score of >3 during the first 3 months. We investigated the impact of high anticholinergic burden on the rate of treatment modification, delirium and mortality in comparison with minimal ACB (ACB score <=1) in propensity-matched cohorts (N = 7438). Approximately 6.0% of patients with dementia were exposed to a high anticholinergic burden within the first three months of treatment. In high anticholinergic burden cohorts, significantly more patients experienced treatment modification (34.9% vs. 32.1%) or delirium (5.6% vs. 3.6%) and the mortality rate was also higher (16.8% vs. 14.1%) than controls. A multivariate Cox proportional hazard regression analysis showed that an average ACB score >3 within the first three months significantly increased the risk of treatment modification (hazard ratio (HR): 1.12, 95% confidence interval (CI): 1.02-1.24), delirium (HR: 1.52, CI: 1.17-1.96) and mortality (HR: 1.23, CI: 1.06-1.41). This study showed that high anticholinergic burden negatively affected the treatment response to cholinesterase inhibitors and that an average ACB score >3 was an independent prognostic factor for delirium or mortality in dementia patients.
ESTHER : Ah_2019_Basic.Clin.Pharmacol.Toxicol_124_741
PubMedSearch : Ah_2019_Basic.Clin.Pharmacol.Toxicol_124_741
PubMedID: 30511428

Title : Identification of Catalposide Metabolites in Human Liver and Intestinal Preparations and Characterization of the Relevant Sulfotransferase, UDP-glucuronosyltransferase, and Carboxylesterase Enzymes - Hwang_2019_Pharmaceutics_11_
Author(s) : Hwang DK , Kim JH , Shin Y , Choi WG , Kim S , Cho YY , Lee JY , Kang HC , Lee HS
Ref : Pharmaceutics , 11 : , 2019
Abstract : Catalposide, an active component of Veronica species such as Catalpa ovata and Pseudolysimachion lingifolium, exhibits anti-inflammatory, antinociceptic, anti-oxidant, hepatoprotective, and cytostatic activities. We characterized the in vitro metabolic pathways of catalposide to predict its pharmacokinetics. Catalposide was metabolized to catalposide sulfate (M1), 4-hydroxybenzoic acid (M2), 4-hydroxybenzoic acid glucuronide (M3), and catalposide glucuronide (M4) by human hepatocytes, liver S9 fractions, and intestinal microsomes. M1 formation from catalposide was catalyzed by sulfotransferases (SULTs) 1C4, SULT1A1*1, SULT1A1*2, and SULT1E1. Catalposide glucuronidation to M4 was catalyzed by gastrointestine-specific UDP-glucuronosyltransferases (UGTs) 1A8 and UGT1A10; M4 was not detected after incubation of catalposide with human liver preparations. Hydrolysis of catalposide to M2 was catalyzed by carboxylesterases (CESs) 1 and 2, and M2 was further metabolized to M3 by UGT1A6 and UGT1A9 enzymes. Catalposide was also metabolized in extrahepatic tissues; genetic polymorphisms of the carboxylesterase (CES), UDP-glucuronosyltransferase (UGT), and sulfotransferase (SULT) enzymes responsible for catalposide metabolism may cause inter-individual variability in terms of catalposide pharmacokinetics.
ESTHER : Hwang_2019_Pharmaceutics_11_
PubMedSearch : Hwang_2019_Pharmaceutics_11_
PubMedID: 31336576

Title : Undibacterium piscinae sp. nov., isolated from Korean shiner intestine - Lee_2019_Int.J.Syst.Evol.Microbiol_69_3148
Author(s) : Lee SY , Kang W , Kim PS , Kim HS , Sung H , Shin NR , Whon TW , Yun JH , Lee JY , Jung MJ , Jeong YS , Tak EJ , Han JE , Hyun DW , Kang MS , Lee KE , Lee BH , Bae JW
Ref : Int J Syst Evol Microbiol , 69 :3148 , 2019
Abstract : A novel Gram-stain-negative, non-spore-forming, obligate aerobic, motile, rod-shaped, and flagellated bacterium, designated S11R28(T), was isolated from the intestinal tract of a Korean shiner, Coreoleuciscus splendidus. Based on 16S rRNA gene sequences, strain S11R28(T) was identified as member of the genus Undibacterium in class Betaproteobacteria, and was closely related to Undibacterium parvum DSM 23061(T) (98.49%). The isolate grew at 4-25 degreesC, pH 6-9, with 0% (w/v) NaCl, and grew optimally at 20 degreesC, pH 8, in the absence of NaCl. The main cellular fatty acids were C(16:0) and summed features 3 (C(16:1)omega7c and/or C(16:1)omega6c). The strain possessed diphosphatidylglycerol, phosphatidylglycerol, and phosphatidylethanolamine as predominant polar lipids, and ubiquinone Q-8 as a respiratory quinone. The polyamine profile composed of 2-hydroxyputrescine, spermidine, putrescine, and benzoic acid. A genomic DNA G+C content was 51.4 mol%. The average nucleotide identity between strains S11R28(T) and U. parvum DSM 23061(T) was 78.66%. Thus, Undibacterium piscinae can be considered a novel species within the genus Undibacterium with the type strain S11R28(T) (=KCTC 62668(T)=JCM 33224(T)).
ESTHER : Lee_2019_Int.J.Syst.Evol.Microbiol_69_3148
PubMedSearch : Lee_2019_Int.J.Syst.Evol.Microbiol_69_3148
PubMedID: 31385778
Gene_locus related to this paper: 9burk-a0a6m4abh3

Title : Potent inhibition of acetylcholinesterase by sargachromanol I from Sargassum siliquastrum and by selected natural compounds - Lee_2019_Bioorg.Chem_89_103043
Author(s) : Lee JP , Kang MG , Lee JY , Oh JM , Baek SC , Leem HH , Park D , Cho ML , Kim H
Ref : Bioorg Chem , 89 :103043 , 2019
Abstract : Six hundred forty natural compounds were tested for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. Of those, sargachromanol I (SCI) and G (SCG) isolated from the brown alga Sargassum siliquastrum, dihydroberberine (DB) isolated from Coptis chinensis, and macelignan (ML) isolated from Myristica fragrans, potently and effectively inhibited AChE with IC50 values of 0.79, 1.81, 1.18, and 4.16microM, respectively. SCI, DB, and ML reversibly inhibited AChE and showed mixed, competitive, and noncompetitive inhibition, respectively, with Ki values of 0.63, 0.77, and 4.46microM, respectively. Broussonin A most potently inhibited BChE (IC50=4.16microM), followed by ML, SCG, and SCI (9.69, 10.79, and 13.69microM, respectively). In dual-targeting experiments, ML effectively inhibited monoamine oxidase B with the greatest potency (IC50=7.42microM). Molecular docking simulation suggested the binding affinity of SCI (-8.6kcal/mol) with AChE was greater than those of SCG (-7.9kcal/mol) and DB (-8.2kcal/mol). Docking simulation indicated SCI interacts with AChE at Trp81, and that SCG interacts at Ser119. No hydrogen bond was predicted for the interaction between AChE and DB. This study suggests SCI, SCG, DB, and ML be viewed as new reversible AChE inhibitors and useful lead compounds for the development for the treatment of Alzheimer's disease.
ESTHER : Lee_2019_Bioorg.Chem_89_103043
PubMedSearch : Lee_2019_Bioorg.Chem_89_103043
PubMedID: 31200287

Title : Comparison of Efficiency of Purification (from Human Plasma) of a Nerve Agent Adduct of Butyrylcholinesterase Between the Affinity Gel Method and Immunomagnetic Separation - Lee_2018_J.Chromatogr.Sci_56_248
Author(s) : Lee JY
Ref : Journal of Chromatography Sci , 56 :248 , 2018
Abstract : O-ethyl S-2-diisopropylaminoethyl methyl phosphonothiolate (VX) is a highly toxic chemical warfare agent because it inhibits cholinesterase (ChE) activity in the nervous system. Inhibition of butyrylcholinesterase (BChE) activity by VX is due to formation of a phosphorylated BChE adduct; this adduct in human plasma can serve as a biomarker of exposure to nerve agents. We compared purification efficiency between the procainamide affinity gel method and immunomagnetic separation (IMS) for the nerve agent adduct of BChE in plasma and then optimized the sample preparation by purifying BChE to measure biomarkers of human exposure to organophosphorus nerve agents. The purification efficiency of IMS was 5-fold greater than that of the procainamide affinity gel method because the antibody conjugate with protein G magnetic beads ensured highly selective capture and high recovery of VX-inhibited BChE from plasma. Protein isolation and extraction of the adduct of VX-inhibited BChE from plasma were made more specific by IMS. A 50 microL of the IMS solution was enough to bind VX-inhibited BChE in up to 0.5 mL of plasma. Nonetheless, the IMS method has a limitation in terms of reutilization of the complexes antibody-magnetic beads. We expect that this approach can be used to quantify other types of organophosphorus adducts in human plasma, thus serving as a possible general assay for biomarkers of exposure to nerve agents.
ESTHER : Lee_2018_J.Chromatogr.Sci_56_248
PubMedSearch : Lee_2018_J.Chromatogr.Sci_56_248
PubMedID: 29244127

Title : The Effects of Donepezil, an Acetylcholinesterase Inhibitor, on Impaired Learning and Memory in Rodents - Shin_2018_Biomol.Ther.(Seoul)_26_274
Author(s) : Shin CY , Kim HS , Cha KH , Won DH , Lee JY , Jang SW , Sohn UD
Ref : Biomol Ther (Seoul) , 26 :274 , 2018
Abstract : A previous study in humans demonstrated the sustained inhibitory effects of donepezil on acetylcholinesterase (AChE) activity; however, the effective concentration of donepezil in humans and animals is unclear. This study aimed to characterize the effective concentration of donepezil on AChE inhibition and impaired learning and memory in rodents. A pharmacokinetic study of donepezil showed a mean peak plasma concentration of donepezil after oral treatment (3 and 10 mg/kg) of approximately 1.2 +/- 0.4 h and 1.4 +/- 0.5 h, respectively; absolute bioavailability was calculated as 3.6%. Further, AChE activity was inhibited by increasing plasma concentrations of donepezil, and a maximum inhibition of 31.5 +/- 5.7% was observed after donepezil treatment in hairless rats. Plasma AChE activity was negatively correlated with plasma donepezil concentration. The pharmacological effects of donepezil are dependent upon its concentration and AChE activity; therefore, we assessed the effects of donepezil on learning and memory using a Y-maze in mice. Donepezil treatment (3 mg/kg) significantly prevented the progression of scopolamine-induced memory impairment in mice. As the concentration of donepezil in the brain increased, the recovery of spontaneous alternations also improved; maximal improvement was observed at 46.5 +/- 3.5 ng/g in the brain. In conclusion, our findings suggest that the AChE inhibitory activity and pharmacological effects of donepezil can be predicted by the concentration of donepezil. Further, 46.5 +/- 3.5 ng/g donepezil is an efficacious target concentration in the brain for treating learning and memory impairment in rodents.
ESTHER : Shin_2018_Biomol.Ther.(Seoul)_26_274
PubMedSearch : Shin_2018_Biomol.Ther.(Seoul)_26_274
PubMedID: 29463072

Title : Physostigmine-loaded liposomes for extended prophylaxis against nerve agent poisoning - Park_2018_Int.J.Pharm_553_467
Author(s) : Park JH , Lee JY , Kim KT , Joe HE , Cho HJ , Shin YK , Kim DD
Ref : Int J Pharm , 553 :467 , 2018
Abstract : Pre-administration of physostigmine can prevent poisoning against nerve agent exposure by reversibly binding to cholinesterase. However, its cholinesterase protection-based prophylactic effect can be eliminated rapidly due to short biological half-life. Liposomes are useful for encapsulating hydrophilic drugs like physostigmine, and can be used for sustained release after parenteral injection. Thus, physostigmine liposomes were prepared by the pH-gradient condition-based remote-loading method for subcutaneous injection. In addition, polyethylene glycol (PEG)-lipid was applied to further extend the release of physostigmine and its prophylactic action. In vitro release of physostigmine, pharmacokinetics and duration of prophylactic effect were then evaluated. Physostigmine was dissolved in distilled water and used as a solution group for comparison. The prepared liposomes showed spherical shape and their particle size was around 130mum. Addition of PEG-lipid in liposomes significantly increased the entrapment efficiency of physostigmine. Both control and PEG liposomes exhibited sustained release pattern compared to the solution. Moreover, the release of PEG liposomes was relatively slower than that of the control liposomes. Pharmacokinetic study in rats revealed that physostigmine liposomes exhibited lower maximum plasma concentration and longer half-life compared to the solution. Plasma cholinesterase inhibition ratio in the liposomal group decreased more gradually compared to the solution. Moreover, PEG liposomes showed higher plasma concentration of physostigmine and cholinesterase inhibition ratio compared to the control liposomes. These results suggest that PEG liposomes have potential to enhance the duration of cholinesterase-protecting effect of physostigmine.
ESTHER : Park_2018_Int.J.Pharm_553_467
PubMedSearch : Park_2018_Int.J.Pharm_553_467
PubMedID: 30389473

Title : Simultaneous Time-concentration Analysis of Soman and VX Adducts to Butyrylcholinesterase and Albumin by LC-MS-MS - Lee_2018_J.Anal.Toxicol_42_293
Author(s) : Lee JY , Kim C , Lee YH
Ref : J Anal Toxicol , 42 :293 , 2018
Abstract : A sensitive method for the purification and determination of two protein adducts, organophosphorus (OP)-BChE and OP-albumin adducts, in a single sample using a simultaneous sample preparation method was developed and validated using liquid chromatography-tandem mass spectrometry. First, we isolated O-ethyl S-2-diisopropylaminoethyl methyl phosphonothiolate (VX) and O-pinacolyl methylphosphonofluoridate (soman, GD)-BChE adducts using an immunomagnetic separation (IMS) method and the HiTrap Blue affinity column was subsequently used to isolate and purify VX and GD-albumin adducts from the plasma of rhesus monkeys exposed to nerve agents. Additionally, we examined the time-concentration profiles of two biomarkers, VX and GD-nonapeptides and VX and GD-tyrosines, derived from OP-BChE and OP-albumin adducts up to 8 weeks after exposure. Based on the results, we determined that VX and GD-tyrosine is more suitable than VX and GD-nonapeptide as a biomarker owing to its longevity. This integrated approach is expected to be applicable for the quantification of other OP-BChE and OP-albumin adducts in human plasma, thus serving as a potential generic assay for exposure to nerve agents.
ESTHER : Lee_2018_J.Anal.Toxicol_42_293
PubMedSearch : Lee_2018_J.Anal.Toxicol_42_293
PubMedID: 29618078

Title : 3,4-Dihydroquinazoline derivatives inhibit the activities of cholinesterase enzymes - Park_2017_Bioorg.Med.Chem.Lett_27_1179
Author(s) : Park B , Nam JH , Kim JH , Kim HJ , Onnis V , Balboni G , Lee KT , Park JH , Catto M , Carotti A , Lee JY
Ref : Bioorganic & Medicinal Chemistry Lett , 27 :1179 , 2017
Abstract : A series of 3,4-dihydroquinazoline derivatives consisting of the selected compounds from our chemical library on the diversity basis and the new synthetic compounds were in vitro tested for their inhibitory activities for both acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum) enzymes. It was discovered that most of the compounds displayed weak AChE and strong BuChE inhibitory activities. In particular, compound 8b and 8d were the most active compounds in the series against BChE with IC50 values of 45nM and 62nM, as well as 146- and 161-fold higher affinity to BChE, respectively. To understand the excellent activity of these compounds, molecular docking simulations were performed to get better insights into the mechanism of binding of 3,4-dihydroquinazoline derivatives. As expected, compound 8b and 8d bind to both catalytic anionic site (CAS) and peripheral site (PS) of BChE with better interaction energy values than AChE, in agreement with our experimental data. Furthermore, the non-competitive/mixed-type inhibitions of both compounds further confirmed their dual binding nature in kinetic studies.
ESTHER : Park_2017_Bioorg.Med.Chem.Lett_27_1179
PubMedSearch : Park_2017_Bioorg.Med.Chem.Lett_27_1179
PubMedID: 28189420

Title : Rivastigmine patch reduces the incidence of postoperative delirium in older patients with cognitive impairment - Youn_2017_Int.J.Geriatr.Psychiatry_32_1079
Author(s) : Youn YC , Shin HW , Choi BS , Kim S , Lee JY , Ha YC
Ref : Int J Geriatr Psychiatry , 32 :1079 , 2017
Abstract : OBJECTIVE: To date, data regarding the efficacy of acetylcholinesterase inhibitors in preventing postoperative delirium (POD) are inconsistent and conflicting. Older individuals with cognitive dysfunction are thought to show POD more frequently. Our aim was to study the effectiveness of rivastigmine prophylaxis on the incidence, severity, and risk factors for POD in older patients with cognitive impairment undergoing hip fracture surgery. METHODS: Of 62 older patients with cognitive impairment about to undergo surgery after a hip fracture, 31 were randomly assigned to receive a rivastigmine patch from 3 days before to 7 days after the operation (Group I), and the other 31 did not receive a rivastigmine patch (Group II). The two groups were compared with regard to incidence and severity of delirium on postoperative days 2 or 3 and 7. Multivariate logistic regression analysis was performed to assess factors associated with POD. RESULTS: Postoperative delirium occurred in five Group I patients and 14 Group II patients (p = 0.013). The mean severity of delirium in the two groups as determined by the Delirium Rating Scale was 2.2 and 6.2 respectively (p = 0.033). The odds ratio for POD was 0.259 (95% CI: 0.074-0.905, p = 0.034) after adjusting for American Society of Anesthesiologists score (p = 0.058), age (p = 0.203), and gender (p = 0.560). There were no rivastigmine-related perioperative complications. CONCLUSION: Perioperative rivastigmine patch application could reduce the occurrence of POD in older patients with low cognitive status. Copyright (c) 2016 John Wiley & Sons, Ltd.
ESTHER : Youn_2017_Int.J.Geriatr.Psychiatry_32_1079
PubMedSearch : Youn_2017_Int.J.Geriatr.Psychiatry_32_1079
PubMedID: 27561376

Title : Incidence and Prevalence of Myasthenia Gravis in Korea: A Population-Based Study Using the National Health Insurance Claims Database - Park_2016_J.Clin.Neurol_12_340
Author(s) : Park SY , Lee JY , Lim NG , Hong YH
Ref : J Clin Neurol , 12 :340 , 2016
Abstract : BACKGROUND AND PURPOSE: There have been a few national population-based epidemiological studies of myasthenia gravis (MG) with wide variation of incidence and prevalence rates worldwide. Herein we report the first nationwide population-based epidemiological study of MG in Korea.
METHODS: We attempted to estimate the incidence and prevalence rates of MG using the Korean National Health Insurance claims database for 2010 to 2013. Cases with MG were defined as those having claim records with a principal diagnosis of MG and the prescription of acetylcholinesterase inhibitors or immunosuppressive agents including corticosteroids and azathioprine within 2 years after the diagnosis. The year 2010 was set as a washout period, such that patients were defined as incident cases if their first records of MG were observed in 2011.
RESULTS: In 2011 there were 1,236 incident cases, and the standardized incidence rate was 2.44 per 100,000 person-years. The standardized prevalence rates were 9.67 and 10.66 per 100,000 persons in 2010 and 2011, respectively. The incidence and prevalence rates peaked in the elderly population aged 60 to 69 years for both sexes.
CONCLUSIONS: This is one of the largest national population-based epidemiological studies of MG, and it has confirmed the high incidence and prevalence rates of MG in the elderly population of South Korea.
ESTHER : Park_2016_J.Clin.Neurol_12_340
PubMedSearch : Park_2016_J.Clin.Neurol_12_340
PubMedID: 27165426

Title : Enrichment of omega-3 fatty acids in cod liver oil via alternate solvent winterization and enzymatic interesterification - Lei_2016_Food.Chem_199_364
Author(s) : Lei Q , Ba S , Zhang H , Wei Y , Lee JY , Li T
Ref : Food Chem , 199 :364 , 2016
Abstract : Enrichment of omega-3 fatty acids in cod liver oil via alternate operation of solvent winterization and enzymatic interesterification was attempted. Variables including separation method, solvent, oil concentration, time and temperature were optimized for the winterization. Meanwhile, Novozyme 435, Lipozyme RM IM and Lipozyme TL IM were screened for interesterification efficiency under different system air condition, time and temperature. In optimized method, alternate winterization (0.1g/mL oil/acetone, 24h, -80 degC, precooled Buchner filtration) and interesterification (Lipozyme TL IM, N2 flow, 2.5h, 40 degC) successfully doubled the omega-3 fatty acid content to 43.20 mol%. (1)H NMR was used to determine omega-3 fatty acid content, and GC-MS to characterize oil product, which mainly contained DHA (15.81 mol%) and EPA (20.23 mol%). The proposed method offers considerable efficiency and reduce production cost drastically. Oil produced thereof is with high quality and of particular importance for the development of omega-3 based active pharmaceutical ingredients.
ESTHER : Lei_2016_Food.Chem_199_364
PubMedSearch : Lei_2016_Food.Chem_199_364
PubMedID: 26775983

Title : Rubus coreanus Miquel Ameliorates Scopolamine-Induced Memory Impairments in ICR Mice - Choi_2014_J.Med.Food_17_1049
Author(s) : Choi MR , Lee MY , Hong JE , Kim JE , Lee JY , Kim TH , Chun JW , Shin HK , Kim EJ
Ref : J Med Food , 17 :1049 , 2014
Abstract : ABSTRACT The present study investigated the effect of Rubus coreanus Miquel (RCM) on scopolamine-induced memory impairments in ICR mice. Mice were orally administrated RCM for 4 weeks and scopolamine was intraperitoneally injected into mice to induce memory impairment. RCM improved the scopolamine-induced memory impairment in mice. The increase of acetylcholinesterase activity caused by scopolamine was significantly attenuated by RCM treatment. RCM increased the levels of acetylcholine in the brain and serum of mice. The expression of choline acetyltransferase, phospho-cyclic AMP response element-binding protein, and phospho-extracellular signal-regulated kinase was significantly increased within the brain of mice treated with RCM. The brain antioxidant enzyme activity decreased by scopolamine was increased by RCM. These results demonstrate that RCM exerts a memory-enhancing effect via the improvement of cholinergic function and the potentiated antioxidant activity in memory-impaired mice. The results suggest that RCM may be a useful agent for improving memory impairment.
ESTHER : Choi_2014_J.Med.Food_17_1049
PubMedSearch : Choi_2014_J.Med.Food_17_1049
PubMedID: 25121635

Title : Butyrylcholinesterase K and Apolipoprotein epsilon4 Affect Cortical Thickness and Neuropsychiatric Symptoms in Alzheimer's Disease - Yoo_2014_Curr.Alzheimer.Res_11_137
Author(s) : Yoo HB , Lee HW , Shin S , Park SW , Choi JS , Jung HY , Cha J , Lee JM , Lee JY
Ref : Curr Alzheimer Res , 11 :137 , 2014
Abstract : Two major genotypes are known to affect the development and progression of Alzheimer's disease (AD) and its response to cholinesterase inhibitors: the apolipoprotein E (ApoE) and butyrylcholinesterase genes (BChE). This study analyzed the effects of the BChE and ApoE genotypes on the cortical thickness of patients with AD and examined how these genotypes affect the neuropsychiatric symptoms of AD. AD-drug-naive patients who met the probable AD criteria proposed by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association were recruited. Of 96 patients with AD, 65 were eligible for cortical thickness analysis. 3D T1-weighted images were acquired, and the cortical regions were segmented using the constrained Laplacian-based automated segmentation with proximities (CLASP) algorithm. Neuropsychiatric symptoms were measured by Neuropsychiatric Inventory (NPI) scores. BChE wild-type carriers (BChE-W) showed more thinning in the left dorsolateral prefrontal cortex, including the lateral premotor regions and anterior cingulate cortex, than did BChE-K variant carriers (BChE-K). ApoE-epsilon4 carriers had a thinner left medial prefrontal cortex, left superior frontal cortex, and left posterior cingulate cortex than did ApoE-epsilon4 non-carriers. Statistical analyses revealed that BChE-K carriers showed significantly less severe aberrant motor behavioral symptoms and that epsilon4 non-carriers showed less severe anxiety and indifference symptoms. The current findings show that, similar to ApoE-epsilon4 non-carriers, BChE-K carriers are protected from the pathological detriments of AD that affect frontal cortical thickness and neuropsychiatric symptoms. This study visually demonstrated the effects of the BChE-K and ApoE genotypes on the structural degeneration and complex aspects of the symptoms of AD.
ESTHER : Yoo_2014_Curr.Alzheimer.Res_11_137
PubMedSearch : Yoo_2014_Curr.Alzheimer.Res_11_137
PubMedID: 24479631

Title : A stress-responsive Escherichia coli protein, CysQ is a highly effective solubility enhancer for aggregation-prone heterologous proteins - Lee_2014_Protein.Expr.Purif_101C_91
Author(s) : Lee JH , Lee JY , Song JA , Han KY , Lee DS , Lee J
Ref : Protein Expr Purif , 101C :91 , 2014
Abstract : When used as an N-terminal fusion expression partner, the Escherichia coli stress-responsive protein, CysQ dramatically increased the cytoplasmic solubility of various aggregation-prone heterologous proteins: Pseudomonas putida cutinase (CUT), human granulocyte colony-stimulating factor (hG-CSF), human ferritin light chain (hFTN-L), arginine deiminase (ADI), human interleukin-2 (IL2), human activation induced cytidine deaminase (AID), and deletion mutant of human glutamate decarboxylase (GAD448-585). As compared with well-known fusion tags such as glutathione-S-transferase (GST) and maltose-binding protein (MBP), the performance of CysQ as solubility enhancer was evidently better than GST and was similar to or better than MBP for the seven heterologous proteins above. This is likely due to the intrinsic ability of CysQ to form its native conformation, probably promoting the binding of molecular chaperones during the folding of CysQ-fusion protein. When used as a substrate, p-nitrophenyl butyrate (PNB) was successfully hydrolyzed to p-nitrophenol by CysQ-CUT fusion mutant. Even after CysQ was removed, the solubility of hFTN-L and hG-CSF, the secondary structure of hG-CSF, and self-assembly activity of hFTN-L were successfully maintained. Conclusively, it seems that CysQ is a highly effective solubility enhancer and fusion expression partner for the production of a variety of bio-active recombinant proteins.
ESTHER : Lee_2014_Protein.Expr.Purif_101C_91
PubMedSearch : Lee_2014_Protein.Expr.Purif_101C_91
PubMedID: 24945073

Title : Interaction Effects of Lipoprotein Lipase Polymorphisms with Lifestyle on Lipid Levels in a Korean Population: A Cross-sectional Study - Pyun_2012_Genomics.Inform_10_88
Author(s) : Pyun JA , Kim S , Park K , Baik I , Cho NH , Koh I , Lee JY , Cho YS , Kim YJ , Go MJ , Shim E , Kwack K , Shin C
Ref : Genomics Inform , 10 :88 , 2012
Abstract : Lipoprotein lipase LPL plays an essential role in the regulation of high-density lipoprotein cholesterol HDLC and triglyceride levels which have been closely associated with cardiovascular diseases Genetic studies in European have shown that LPL single-nucleotide polymorphisms SNPs are strongly associated with lipid levels However studies about the influence of interactions between LPL SNPs and lifestyle factors have not been sufficiently performed Here we examine if LPL polymorphisms as well as their interaction with lifestyle factors influence lipid concentrations in a Korean population A two-stage association study was performed using genotype data for SNPs on the LPL gene including the 3 flanking region from 7,536 stage 1 and 3,703 stage 2 individuals The association study showed that 15 SNPs and 4 haplotypes were strongly associated with HDLC lowest p 2.86 x 10(-22 and triglyceride levels lowest p 3.0 x 10(-15 Interactions between LPL polymorphisms and lifestyle factors lowest p 9.6 x 10(-4 were also observed on lipid concentrations These findings suggest that there are interaction effects of LPL polymorphisms with lifestyle variables including energy intake fat intake smoking and alcohol consumption as well as effects of LPL polymorphisms themselves on lipid concentrations in a Korean population.
ESTHER : Pyun_2012_Genomics.Inform_10_88
PubMedSearch : Pyun_2012_Genomics.Inform_10_88
PubMedID: 23105935

Title : Human adipose tissue-derived mesenchymal stem cells: characteristics and therapeutic potential as cellular vehicles for prodrug gene therapy against brainstem gliomas - Choi_2012_Eur.J.Cancer_48_129
Author(s) : Choi SA , Lee JY , Wang KC , Phi JH , Song SH , Song J , Kim SK
Ref : Eur J Cancer , 48 :129 , 2012
Abstract : Human mesenchymal stem cells (hMSCs) have emerged as attractive cellular vehicles for gene therapy against brain malignancy because of their targeted tropism for cancer and the intrinsic attribute of autologous transplantation. We evaluated the characteristics and therapeutic potential of human adipose tissue-derived MSCs (hAT-MSCs) and prodrug gene therapy against diffuse pontine gliomas. The hAT-MSCs were isolated from human adipose tissue and characterised for morphology, surface markers and potential to differentiate into mesenchymal and neuronal lineages. We genetically modified hAT-MSCs to express rabbit carboxylesterase (rCE) enzyme, which can efficiently convert the prodrug CPT-11 (irinotecan-7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin), into the active drug SN-38 (7-ethyl-10-hydroxycamptothecin). The migratory capacity of hAT-MSCs expressing rCE (hAT-MSC.rCE), their ability to convert CPT-11 to SN-38 and cytotoxic effect on F98 cells were evaluated in vitro. The therapeutic potential of hAT-MSC.rCE was confirmed using a rat brainstem glioma model. The hAT-MSCs showed fibroblast-like morphology and expressed hMSC-specific markers including CD73, CD90 and CD105. The hAT-MSCs could differentiate into a mesenchymal lineage and transdifferentiate into a neuronal lineage under optimum culture conditions. The hAT-MSC.rCE converted CPT-11 to SN-38 and preserved the tumour tropism of hAT-MSCs. Brainstem glioma-bearing rats treated with hAT-MSC.rCE and CPT-11 survived 5d more than rats treated with CPT-11 only (p=0.0018). Our study demonstrates that hAT-MSCs can be easily prepared and genetically modified as cellular vehicles for prodrug gene therapy and that they have therapeutic potential against brainstem gliomas.
ESTHER : Choi_2012_Eur.J.Cancer_48_129
PubMedSearch : Choi_2012_Eur.J.Cancer_48_129
PubMedID: 21664124

Title : Discovery of DA-1229: a potent, long acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes - Kim_2011_Bioorg.Med.Chem.Lett_21_3809
Author(s) : Kim HJ , Kwak WY , Min JP , Lee JY , Yoon TH , Kim HD , Shin CY , Kim MK , Choi SH , Kim HS , Yang EK , Cheong YH , Chae YN , Park KJ , Jang JM , Choi SJ , Son MH , Kim SH , Yoo M , Lee BJ
Ref : Bioorganic & Medicinal Chemistry Lett , 21 :3809 , 2011
Abstract : A series of beta-amino amide containing substituted piperazine-2-one derivatives was synthesized and evaluated as inhibitors of dipeptidyl pepdidase-4 (DPP-4) for the treatment of type 2 diabetes. As results of intensive SAR study of the series, (R)-4-[(R)-3-amino-4-(2,4,5-trifluorophenyl)-butanoyl]-3-(t-butoxymethyl)-piperaz in-2-one (DA-1229) displayed potent DPP-4 inhibition pattern in several animal models, was selected for clinical development.
ESTHER : Kim_2011_Bioorg.Med.Chem.Lett_21_3809
PubMedSearch : Kim_2011_Bioorg.Med.Chem.Lett_21_3809
PubMedID: 21570283

Title : Genome-wide scan of granular corneal dystrophy, type II: confirmation of chromosome 5q31 and identification of new co-segregated loci on chromosome 3q26.3 - Lee_2011_Exp.Mol.Med_43_393
Author(s) : Lee EJ , Kim KJ , Kim HN , Bok J , Jung SC , Kim EK , Lee JY , Kim HL
Ref : Exp Mol Med , 43 :393 , 2011
Abstract : Granular corneal dystrophy, type II (CGD2; Avellino corneal dystrophy) is the most common corneal dystrophy among Koreans, but its pathophysiology is still poorly understood. Many reports showed that even though the causative mutation is the same TGFBI R124H mutation, there are severe and mild phenotypes of the corneal dystrophy. We also observed the phenotype differences in our samples. For this reason, we focused our effort on the identification of unknown genetic factor related to phenotype variation. A total 551 individuals from 59 families were genotyped with SNP chip and used in genome-wide linkage analysis. From single-point linkage analyses, we confirmed the known 5q31 region for TGFBI gene, and selected novel nine candidate loci for CGD2. In simulation analysis, the only 3q26.3 region including neuroligin 1 gene (NLGN1) was supported by empirical statistic significance. To investigate the effect of genetic heterogeneity in linkage analysis, we classified CGD2 families into two subgroups. Although we could not find a significant evidence for correlation between the 3q26.3 region and CGD2 phenotypes, this first genome-wide analysis with CGD2 families in Korea has a very important value for offering insights in genetics of CGD2. In addition, the co-segregating loci with CGD2 including 3q26.3 would be a good target for further study to understand the pathophysiology of CGD2.
ESTHER : Lee_2011_Exp.Mol.Med_43_393
PubMedSearch : Lee_2011_Exp.Mol.Med_43_393
PubMedID: 21628991

Title : Therapeutic targeting of subdural medulloblastomas using human neural stem cells expressing carboxylesterase - Lim_2011_Cancer.Gene.Ther_18_817
Author(s) : Lim SH , Choi SA , Lee JY , Wang KC , Phi JH , Lee DH , Song SH , Song JH , Jin X , Kim H , Lee HJ , Lim I , Kim SU , Kim SK
Ref : Cancer Gene Therapy , 18 :817 , 2011
Abstract : The prognosis of medulloblastoma has improved significantly because of advances in multi-modal treatments; however, metastasis remains one of the prognostic factors for a poor outcome and is usually associated with tumor recurrence. We evaluated the migratory potential and therapeutic efficacy of genetically engineered human neural stem cells (NSCs) that encode a prodrug enzyme in the subdural medulloblastoma model. We genetically modified HB1.F3 (F3) immortalized human NSCs to express rabbit carboxylesterase (rCE) enzyme, which efficiently converts the prodrug CPT-11 (Irinotecan) into an active anti-cancer agent (SN-38). To simulate clinical metastatic medulloblastomas, we implanted human medulloblastoma cells into the subdural spaces of nude mice. rCE expressing NSCs (F3.rCE) were labeled with fluorescence magnetic nanoparticle for in vivo imaging. The therapeutic potential of F3.rCE was confirmed using a mouse subdural medulloblastoma model. The majority of intravenously (i.v.) injected, F3.rCE cells migrated to the subdural medulloblastoma site and a small number of F3.rCE cells were found in the lungs, pancreas, kidney and liver. Animals that received F3.rCE cells in combination with prodrug CPT-11 survived significantly longer (median survival: 142 days) than control mice that received F3.rCE cells only (median survival: 80 days, P<0.001) or CPT-11 only (median survival: 118 days, P<0.001). In conclusion, i.v. injected F3.rCE NSCs were able to target subdural medulloblastomas and demonstrate therapeutic efficacy. Our study provides data that supports further investigation of stem-cell-based gene therapy against metastatic medulloblastomas.
ESTHER : Lim_2011_Cancer.Gene.Ther_18_817
PubMedSearch : Lim_2011_Cancer.Gene.Ther_18_817
PubMedID: 21869821

Title : Genome sequence of Lactobacillus johnsonii PF01, isolated from piglet feces - Lee_2011_J.Bacteriol_193_5030
Author(s) : Lee JH , Chae JP , Lee JY , Lim JS , Kim GB , Ham JS , Chun J , Kang DK
Ref : Journal of Bacteriology , 193 :5030 , 2011
Abstract : Lactobacillus johnsonii PF01, an autochthonous bacterium of the gastrointestinal tract, was isolated from a fecal sample from a piglet. The strain adhered specifically to the duodenal and jejunal epithelial cells of the piglet and had high bile resistance activity. Here we report the genomic sequence of L. johnsonii PF01.
ESTHER : Lee_2011_J.Bacteriol_193_5030
PubMedSearch : Lee_2011_J.Bacteriol_193_5030
PubMedID: 21742886
Gene_locus related to this paper: lacga-q047a5

Title : Effects of BT-11 on memory in healthy humans - Lee_2009_Neurosci.Lett_454_111
Author(s) : Lee JY , Kim KY , Shin KY , Won BY , Jung HY , Suh YH
Ref : Neuroscience Letters , 454 :111 , 2009
Abstract : We previously reported that BT-11, the extract of dried roots of Polygala tenuifolia Willdenow, had neuroprotective effects and improved scopolamine- and stress-induced amnesia in rats. It also blocked the activity of acetylcholinesterase and enhanced glucose utilization in the rat brain. Therefore, we examined whether BT-11 could enhance memory in healthy humans. This study was a randomized, double-blind, placebo-controlled, parallel-group study of BT-11 in healthy adults. The participants were given capsules of BT-11 or placebo 3 times daily for 4 weeks. The Korean version of the California Verbal Learning Test (K-CVLT) and the Self-Ordered Pointing Test (SOPT) were used to assess verbal memory and working memory, respectively. The subjects in BT-11-treated group showed more significant increases in immediate recall on the K-CVLT than those in the placebo-treated group. In a comparison within each group, the subjects' scores on most subtests of the K-CVLT were significantly increased by both placebo and BT-11 treatment. Interestingly, the subjects' scores on the recognition subtest of the K-CVLT were significantly increased by BT-11 treatment but not by placebo treatment. Also, BT-11 treatment significantly reduced the number of errors on the SOPT, whereas placebo treatment did not. We are the first to show that BT-11 has memory-enhancing effects and may be a memory-enhancing drug in healthy adults.
ESTHER : Lee_2009_Neurosci.Lett_454_111
PubMedSearch : Lee_2009_Neurosci.Lett_454_111
PubMedID: 19429065

Title : BT-11 is effective for enhancing cognitive functions in the elderly humans - Shin_2009_Neurosci.Lett_465_157
Author(s) : Shin KY , Lee JY , Won BY , Jung HY , Chang KA , Koppula S , Suh YH
Ref : Neuroscience Letters , 465 :157 , 2009
Abstract : Roots of Polygala tenuifolia Willdenow have been used in humans for centuries because of its sedative effects. We previously reported that BT-11, extracted from the roots of the plant, improved memory impairments in rats, enhanced memory in normal humans, and inhibited acetylcholinesterase activities in vitro. The present study was a randomized, double-blind, placebo-controlled comparison study to investigate whether BT-11 could enhance memory in the elderly humans. We used the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet (CERAD) and the Mini-Mental State Examination (MMSE). In the elderly, the total CERAD scores were much more significantly increased in the BT-11-treated group (n=28) than in the placebo-treated group (n=25). Especially, the mean scores of word list recognition, constructional recall and praxis, and modified Boston naming test were markedly improved in BT-11-treated group than in placebo-treated group. In conclusion, BT-11 could enhance some cognitive functions including memory in the elderly humans and therefore may be used as nutraceuticals that provide health benefits, including disease prevention and/or treatment.
ESTHER : Shin_2009_Neurosci.Lett_465_157
PubMedSearch : Shin_2009_Neurosci.Lett_465_157
PubMedID: 19699261

Title : Cloning and characterization of canine thyroglobulin complementary DNA - Lee_2007_Domest.Anim.Endocrinol_32_178
Author(s) : Lee JY , Uzuka Y , Tanabe S , Sarashina T , Suzuki H , Sato M
Ref : Domest Anim Endocrinol , 32 :178 , 2007
Abstract : Canine thyroglobulin (cTg) is one of the thyroid autoantigens associated with hypothyroidism caused by autoimmune thyroiditis in dog. To identify canine-specific areas in cTg, we cloned, by reverse transcriptase PCR, and sequenced the complete cDNA of cTg. It revealed an open reading frame of 8289 nucleotides, which encode a polypeptide of 2762 amino acids that is 78.9 and 78.1% identical to bovine and human thyroglobulin, respectively. This complete cTg sequence may be useful to promote the understanding of the primary structure of cTg and, it will be informative data in the further search about antigenic epitopes associated with autoimmune thyroiditis and pathogenesis of cTg-associated thyroid diseases in dog.
ESTHER : Lee_2007_Domest.Anim.Endocrinol_32_178
PubMedSearch : Lee_2007_Domest.Anim.Endocrinol_32_178
PubMedID: 16806791
Gene_locus related to this paper: canfa-q1ert3

Title : Effects of manufactured soluble dietary fiber from Quercus mongolica on hepatic HMG-CoA reductase and lipoprotein lipase activities in epididymal adipose tissue of rats fed high cholesterol diets - Chai_2003_J.Med.Food_6_329
Author(s) : Chai YM , Lim BK , Lee JY , Kim MN , Park MR , Rhee SJ
Ref : J Med Food , 6 :329 , 2003
Abstract : This study investigated the effect of a manufactured soluble dietary fiber on lipid metabolism in rats fed high cholesterol diets. Soluble dietary fiber was prepared from wood chips of oak (Quercus mongolica). Male Sprague-Dawley rats weighing 100 +/- 10 g were randomly assigned to either a normal diet or five high cholesterol diets containing 1% cholesterol and different fiber supplements. The high cholesterol groups were subdivided into fiber-free diet (FF), 5% pectin (5P), 10% pectin (10P), 5% manufactured soluble dietary fiber (5QM), and 10% manufactured soluble dietary fiber (10QM) groups. Total serum cholesterol concentrations in all soluble dietary fiber-supplemented groups were lower than in the FF group. The high-density lipoprotein-cholesterol concentration in the FF group was significantly lower, compared with the normal group, but was increased in groups supplemented with soluble dietary fiber. Low-density lipoprotein-cholesterol levels and the atherogenic index had the same tendency as total cholesterol concentration. Compared with the FF group, in the 5P, 5QM, 10P, and 10QM groups hepatic triglyceride concentrations were 12%, 16%, 20%, and 24% lower, respectively, and hepatic cholesterol concentrations were 48%, 52%, 52%, and 58% lower, respectively. Hepatic 3-hydroxy-3-methylglutaryl-CoA reductase activity in the soluble fiber groups was significantly higher than in the FF groups, but lower than the normal group. When hepatic tissue was observed under a light microscope, the FF group had completely formed lipomas in the hepatic tissue, which led to fat deposits and then a fatty liver. The size and number of lipomas were lower in the soluble dietary fiber-fed groups, as compared with the group not fed dietary fiber. In conclusion, improvements in lipid metabolism were observed as a result of the manufactured soluble dietary fiber from the oak chips, and were similar to that seen for pectin. The preparation method for the soluble dietary fiber from oak chips successfully produced a functional soluble fiber.
ESTHER : Chai_2003_J.Med.Food_6_329
PubMedSearch : Chai_2003_J.Med.Food_6_329
PubMedID: 14977441

Title : Synthesis and biological evaluation of novel A-ring modified hexacyclic camptothecin analogues - Kim_2001_J.Med.Chem_44_1594
Author(s) : Kim DK , Ryu DH , Lee JY , Lee N , Kim YW , Kim JS , Chang K , Im GJ , Kim TK , Choi WS
Ref : Journal of Medicinal Chemistry , 44 :1594 , 2001
Abstract : Eleven A-ring modified hexacyclic analogues of camptothecin (CPT) containing a 1,4-oxazine ring were synthesized from 10-hydroxycamptothecin (11a) and 7-ethyl-10-hydroxycamptothecin (3) (SN-38) in four to five steps and were subjected to the biological tests such as cytotoxicity, topoisomerase I (Topo I) inhibitory activity, acetylcholinesterase (AChE) inhibition, and stability in human plasma. Four compounds 15a, 15b, 16a, and 16c were about 2-fold more potent than topotecan and as potent as CPT toward human cancer cell lines A549, H128, WiDr, MKN45, SK-OV-3, and SK-BR-3 in vitro, even though the most active compound 15b was slightly less potent than SN-38. The potency of Topo I inhibition of these compounds showed relatively good correlation with their cytotoxicity. Most of the compounds exhibited AChE inhibitory activity weaker (9 +/- 2 to 20 +/- 3%) than CPT (23 +/- 5%) or topotecan (20 +/- 4%) and similar to SN-38 (13 +/- 2%), indicating that they might have little effect on causing early diarrhea. The stability of lactone forms of these compounds in human plasma seemed to be much higher than that of CPT and similar to that of topotecan but lower than that of SN-38. Among the new hexacyclic CPT analogues, compound 15b showed higher antitumor activity against human tumor xenograft, WiDr, in nude mice compared to that of SN-38. The most promising compound 15b has been selected for further development.
ESTHER : Kim_2001_J.Med.Chem_44_1594
PubMedSearch : Kim_2001_J.Med.Chem_44_1594
PubMedID: 11334569

Title : Characterization of the dnaG locus in Mycobacterium smegmatis reveals linkage of DNA replication and cell division - Klann_1998_J.Bacteriol_180_65
Author(s) : Klann AG , Belanger AE , Abanes-De Mello A , Lee JY , Hatfull GF
Ref : Journal of Bacteriology , 180 :65 , 1998
Abstract : We have isolated a UV-induced temperature-sensitive mutant of Mycobacterium smegmatis that fails to grow at 42 degrees C and exhibits a filamentous phenotype following incubation at the nonpermissive temperature, reminiscent of a defect in cell division. Complementation of this mutant with an M. smegmatis genomic library and subsequent subcloning reveal that the defect lies within the M. smegmatis dnaG gene encoding DNA primase. Sequence analysis of the mutant dnaG allele reveals a substitution of proline for alanine at position 496. Thus, dnaG is an essential gene in M. smegmatis, and DNA replication and cell division are coupled processes in this species. Characterization of the sequences flanking the M. smegmatis dnaG gene shows that it is not part of the highly conserved macromolecular synthesis operon present in other eubacterial species but is part of an operon with a dgt gene encoding dGTPase. The organization of this operon is conserved in Mycobacterium tuberculosis and Mycobacterium leprae, suggesting that regulation of DNA replication, transcription, and translation may be coordinated differently in the mycobacteria than in other bacteria.
ESTHER : Klann_1998_J.Bacteriol_180_65
PubMedSearch : Klann_1998_J.Bacteriol_180_65
PubMedID: 9422594

Title : Isolation and analysis of metA, a methionine biosynthetic gene encoding homoserine acetyltransferase in corynebacterium glutamicum - Park_1998_Mol.Cells_8_286
Author(s) : Park SD , Lee JY , Kim Y , Kim JH , Lee HS
Ref : Mol Cells , 8 :286 , 1998
Abstract : The metA gene encoding homoserine acetyltransferase, the first enzyme of the methionine biosynthetic pathway, was isolated from a pMT1-based corynebacterium glutamicum gene library via complementation of an Escherichia coli metA mutant. A DNA-sequence analysis of the cloned DNA is identified an open-reading frame of 1,137 bp which encodes a protein with the molecular weight of 41,380 comprising 379 amino acids. The putative protein product showed good amino acid-sequence homology to its counterpart in other organisms. The internal fragment of the cloned DNA was successfully used to disrupt chromosomal metA, demonstrating the identity of the cloned gene. The C. glutamicum metA mutant lost the ability to grow on glucose minimal medium supplemented with homoserine. However, the mutant could grow on a minimal medium supplemented with cystathionine, demonstrating that C. glutamicum uses the cystathionine route to synthesize methionine. Introduction of a plasmid carrying cloned metA into C. glutamicum resulted in a 10-fold increase in enzyme activities and expression of a protein product of M(r) 41,000, which agrees with the sequence data and is similar in size to those of other homoserine acetyltransferases. Unlike E. coli whose metA product uses succinyl coenzyme A as a substrate, the cloned metA gene produced homoserine acetyltransferase which uses only acetyl coenzyme A as the acyl donor.
ESTHER : Park_1998_Mol.Cells_8_286
PubMedSearch : Park_1998_Mol.Cells_8_286
PubMedID: 9666465
Gene_locus related to this paper: corgl-metx

Title : Organ culture with proinflammatory cytokines reproduces impairment of the beta-adrenoceptor-mediated relaxation in tracheas of a guinea pig antigen model - Wills-Karp_1993_Am.J.Respir.Cell.Mol.Biol_8_153
Author(s) : Wills-Karp M , Uchida Y , Lee JY , Jinot J , Hirata A , Hirata F
Ref : American Journal of Respiratory Cellular & Molecular Biology , 8 :153 , 1993
Abstract : The challenge of previously sensitized guinea pigs with aerosolized ovalbumin resulted in impairment of the beta-adrenoceptor-mediated relaxation as measured by the in vitro isometric assay of tracheas preconstricted with endothelin-1 or carbamylcholine. Numbers and affinities of beta-adrenoceptors in lung membranes of these animals were not altered under these conditions, although the antigen challenge caused an inflammatory response, as evident from the accumulation of inflammatory cells in the bronchoalveolar lavage fluids. In order to investigate the pathophysiologic role of inflammation in hyperreactive airways, isolated guinea pig tracheas were cultured with proinflammatory cytokines such as human recombinant tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), or interleukin-2 (IL-2). None of these cytokines affected the contractile response of tracheas to carbamylcholine. After preconstriction with carbamylcholine, the TNF-alpha- and IL-1 beta-pretreated tissues produced a significant reduction in the maximal relaxation induced by isoproterenol, whereas the IL-2 pretreatment had no effect. The reduction of the isoproterenol-mediated relaxation by the IL-1 beta treatment was time and dose dependent. Our present observations suggest that in vitro incubation of naive tracheas with proinflammatory cytokines is able to reproduce apparent beta-adrenoceptor impairment as seen in the airways of antigen-challenged guinea pigs of asthma model.
ESTHER : Wills-Karp_1993_Am.J.Respir.Cell.Mol.Biol_8_153
PubMedSearch : Wills-Karp_1993_Am.J.Respir.Cell.Mol.Biol_8_153
PubMedID: 8381292