Kim MS

References (23)

Title : Identification of promising inhibitory heterocyclic compounds against acetylcholinesterase using QSAR, ADMET, biological activity, and molecular docking - Nguyen_2023_Comput.Biol.Chem_104_107872
Author(s) : Nguyen HD , Kim MS
Ref : Comput Biol Chem , 104 :107872 , 2023
Abstract : Heterocyclic compounds exert diverse functions, especially acetylcholinesterase (AChE) inhibition. Thus, identifying the association between their detailed structures and biological activities is important to the development of novel medications for Alzheimer's disease (AD) treatment. In this study, diverse sets of 120 potent and selective heterocyclic compounds (-log[the halfmaximal inhibitory concentration] (pIC50) values ranged from 8.01 to 12.50) were used to develop quantitative structure-activity relationship (QSAR) models using multiple linear regression (MLR), multiple nonlinear regression (MNLR), Bayesian model average (BMA), and artificial neural network (ANN) models. The models' robustness and stability have been assessed using both internal and external methodology. ANN outperforms MLR, MNLR, and BMA according to external validation. The molecular descriptors incorporated into the model were in satisfactory correlation with the AChE receptor-ligand complex X-ray structures, making the model interpretable and predictive. Three selected compounds exert drug-like characteristics (pIC50 values ranged from 11.01 to 11.17). The binding affinity between the optimal compounds and the AChE receptor (RCSB ID 3LII) ranged from - 7.4 to - 8.8 kcal/mol. Remarkably, the pharmacokinetics, physicochemical properties, and biological activities of compound 25 (C23H32N2O2, PubChem CID 118727071, pIC50 value = 11.17) were found to be consistent with its therapeutic effects in AD due to its cholinergic and non-toxic nature, non-P-glycoprotein, high gastrointestinal absorption, and capability to penetrate the blood-brain barrier.
ESTHER : Nguyen_2023_Comput.Biol.Chem_104_107872
PubMedSearch : Nguyen_2023_Comput.Biol.Chem_104_107872
PubMedID: 37119698

Title : Pretreatment of rhesus monkeys with transdermal patches containing physostigmine and procyclidine: implications of the delivery system for the potential application against VX nerve agent intoxication in humans - Nam_2023_Arch.Toxicol__
Author(s) : Nam JH , Kim MS , Song YJ , Kim CH , Kim WS , Yu CH , Joe HE , Hur GH , Seo MR , Kim Y , Park KE , Choi JY , Chung SJ , Shin YK
Ref : Archives of Toxicology , : , 2023
Abstract : Physostigmine (Phs) is a reversible inhibitor of acetylcholinesterase (AChE) that penetrates the blood-brain barrier (BBB) and could be used to protect the central nervous system (CNS) against the effects of nerve agents. For prophylactic effectiveness, long, steady, and adequate inhibition of AChE activity by Phs is needed to broadly protect against the CNS effects of nerve agents. Here, we evaluated the efficacy of transdermal patches containing Phs and procyclidine (PC) as prophylactic agents. Patches (25 cm(2)) containing 4.4smg Phs and 17.8smg PC had a protective ratio of approximately 78.6-fold in rhesus monkeys challenged with VX nerve agent and given an antidote. Physiologically based pharmacokinetic model in conjunction with an indirect pharmacodynamic (PBPK/PD) was developed for Phs and scaled to rhesus monkeys. The model was able to reproduce the concentration profile and inhibitory effect on AChE of Phs in monkeys, as evidenced by correlation coefficients of 0.994 and 0.992 for 25 cm(2) and 49 cm(2) patches, respectively (i.e., kinetic data), and 0.989 and 0.968 for 25 cm(2) and 49 cm(2) patches, respectively (i.e., dynamic data). By extending the monkey PBPK/ PD model to humans, the effective human dose was predicted to be five applications of a 25 cm(2) patch (i.e., 22smg Phs), and two applications of a 49scm(2) patch (i.e., 17.4smg Phs). Therefore, given that patch application of Phs in rhesus monkeys has a prolonged effect (namely, AChE inhibition of 19.6% for the 25 cm(2) patch and 23.0% for the 49 cm(2) patch) for up to 216sh, patch formulation of Phs may provide similar protection against nerve agent intoxication in humans.
ESTHER : Nam_2023_Arch.Toxicol__
PubMedSearch : Nam_2023_Arch.Toxicol__
PubMedID: 36633609

Title : Mumefural Improves Recognition Memory and Alters ERK-CREB-BDNF Signaling in a Mouse Model of Chronic Cerebral Hypoperfusion - Kim_2023_Nutrients_15_
Author(s) : Kim MS , Kim BY , Kim JI , Lee J , Jeon WK
Ref : Nutrients , 15 : , 2023
Abstract : Cognitive impairment resulting from chronic cerebral hypoperfusion (CCH) is known as vascular dementia (VaD) and is associated with cerebral atrophy and cholinergic deficiencies. Mumefural (MF), a bioactive compound found in a heated fruit of Prunus mume Sieb. et Zucc, was recently found to improve cognitive impairment in a rat CCH model. However, additional evidence is necessary to validate the efficacy of MF administration for treating VaD. Therefore, we evaluated MF effects in a mouse CCH model using unilateral common carotid artery occlusion (UCCAO). Mice were subjected to UCCAO or sham surgery and orally treated with MF daily for 8 weeks. Behavioral tests were used to investigate cognitive function and locomotor activity. Changes in body and brain weights were measured, and levels of hippocampal proteins (brain-derived neurotrophic factor (BDNF), extracellular signal-regulated kinase (ERK), cyclic AMP-response element-binding protein (CREB), and acetylcholinesterase (AChE)) were assessed. Additionally, proteomic analysis was conducted to examine the alterations in protein profiles induced by MF treatment. Our study showed that MF administration significantly improved cognitive deficits. Brain atrophy was attenuated and MF treatment reversed the increase in AChE levels. Furthermore, MF significantly upregulated p-ERK/ERK, p-CREB/CREB, and BDNF levels after UCCAO. Thus, MF treatment ameliorates CCH-induced cognitive impairment by regulating ERK/CREB/BDNF signaling, suggesting that MF is a therapeutic candidate for treating CCH.
ESTHER : Kim_2023_Nutrients_15_
PubMedSearch : Kim_2023_Nutrients_15_
PubMedID: 37513692

Title : In silico exploration of promising heterocyclic molecules against both acetylcholinesterase and butyrylcholinesterase enzymes - Nguyen_2023_J.Biomol.Struct.Dyn__1
Author(s) : Nguyen HD , Kim MS
Ref : J Biomol Struct Dyn , :1 , 2023
Abstract : We aimed to further explore the relationship between heterocyclic molecules and their associated biological activities for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. A dataset of 36 heterocycles was used to predict the activity of AChE and BChE inhibitors (the pIC50 values ranged from 7.84 to 12.49). A quantitative structure-activity relationship (QSAR) study was generated with the help of four different models (BMA, MNLR, MLR, and ANN). Four of the models were statistically acceptable based on both internal and external validation. The descriptors used in the models were similar to the X-ray structures of the target-ligand complexes, which made it possible to predict the pIC50 for AChE and BChE enzymes. Five selected molecules (compounds 6 (C(21)H(21)F(3)N(4)O), compound 7 (C(22)H(23)F(3)N(4)O), and compound 8 (C(22)H(23)F(3)N(4)O(2)) belong to the oxadiazole derivative group; compound 16 (C(17)H(13)ClN(2)O(3)) is classified into the chemical structures of different N, O, and S-based heterocycle groups; and compound 25 (C(19)H(17)NO(2)) pertains to the pyrimidine derivative group) possessed high pIC50 values for AChE and BChE enzymes (pIC50 values for AChE and BChE ranged from 9.01 to 10.32). The range of docking scores between the AChE and BChE receptors and their respective candidates was from -8.1 to -9.2 kcal/mol. The pharmacokinetics, biological activities, and physicochemical properties of five selected compounds supported their ability to protect against AD because they are not toxic, have a cholinergic effect, can cross the blood-brain barrier, and are well absorbed by the gastrointestinal tract.Communicated by Ramaswamy H. Sarma.
ESTHER : Nguyen_2023_J.Biomol.Struct.Dyn__1
PubMedSearch : Nguyen_2023_J.Biomol.Struct.Dyn__1
PubMedID: 37477246

Title : Paradoxical pulmonary hemorrhage associated with hemocoagulase batroxobin in a patient with hemoptysis: A CARE-compliant case report - Kim_2021_Medicine.(Baltimore)_100_e24040
Author(s) : Kim TO , Kim MS , Kho BG , Park HY , Kwon YS , Kim YI , Lim SC , Shin HJ
Ref : Medicine (Baltimore) , 100 :e24040 , 2021
Abstract : RATIONAL: Hemocoagulase, a hemostatic, is used in patients with trauma, gastrointestinal bleeding, or pulmonary hemorrhage or those undergoing surgery. However, paradoxical bleeding after hemocoagulase administration is not considered a clinically significant adverse effect. Here, we report a case of paradoxical pulmonary hemorrhage associated with hypofibrinogenemia after administration of the hemocoagulase batroxobin in a patient with hemoptysis. PATIENT CONCERNS: An 86-year-old woman complained of hemoptysis during hospitalization with organophosphate poisoning. Hemocoagulase was administered to manage bleeding; however, bleeding signs, such as hemoptysis, massive epistaxis, and ecchymosis, recurred. DIAGNOSES: The patient was diagnosed with acquired hypofibrinogenemia on the basis of the reduced plasma fibrinogen level after hemocoagulase administration and lack of other causes of bleeding. INTERVENTION: Hemocoagulase administration was discontinued, and fibrinogen-containing plasma products were administered. OUTCOMES: The plasma fibrinogen level normalized and bleeding signs did not recur. LESSONS: It is necessary to measure plasma fibrinogen levels regularly in patients undergoing hemocoagulase administration and discontinue its administration when acquired hypofibrinogenemia is detected.
ESTHER : Kim_2021_Medicine.(Baltimore)_100_e24040
PubMedSearch : Kim_2021_Medicine.(Baltimore)_100_e24040
PubMedID: 33530198

Title : Unprecedented Noncanonical Features of the Nonlinear Nonribosomal Peptide Synthetase Assembly Line for WS9326A Biosynthesis - Kim_2021_Angew.Chem.Int.Ed.Engl_60_19766
Author(s) : Kim MS , Bae M , Jung YE , Kim JM , Hwang S , Song MC , Ban YH , Bae ES , Hong S , Lee SK , Cha SS , Oh DC , Yoon YJ
Ref : Angew Chem Int Ed Engl , 60 :19766 , 2021
Abstract : Systematic inactivation of nonribosomal peptide synthetase (NRPS) domains and translocation of the thioesterase (TE) domain revealed several unprecedented nonlinear NRPS assembly processes during the biosynthesis of the cyclodepsipeptide WS9326A in Streptomyces sp. SNM55. First, two sets of type II TE (TEII)-like enzymes mediate the shuttling of activated amino acids between two sets of stand-alone adenylation (A)-thiolation (T) didomain modules and an "A-less" condensation (C)-T module with distinctive specificities and flexibilities. This was confirmed by the elucidation of the affinities of the A-T didomains for the TEIIs and its structure. Second, the C-T didomain module operates iteratively and independently from other modules in the same protein to catalyze two chain elongation cycles. Third, this biosynthetic pathway includes the first example of module skipping, where the interpolated C and T domains are required for chain transfer.
ESTHER : Kim_2021_Angew.Chem.Int.Ed.Engl_60_19766
PubMedSearch : Kim_2021_Angew.Chem.Int.Ed.Engl_60_19766
PubMedID: 33963654
Gene_locus related to this paper: 9actn-a0a49v3j7

Title : Genome Sequence of Striga asiatica Provides Insight into the Evolution of Plant Parasitism - Yoshida_2019_Curr.Biol_29_3041
Author(s) : Yoshida S , Kim S , Wafula EK , Tanskanen J , Kim YM , Honaas L , Yang Z , Spallek T , Conn CE , Ichihashi Y , Cheong K , Cui S , Der JP , Gundlach H , Jiao Y , Hori C , Ishida JK , Kasahara H , Kiba T , Kim MS , Koo N , Laohavisit A , Lee YH , Lumba S , McCourt P , Mortimer JC , Mutuku JM , Nomura T , Sasaki-Sekimoto Y , Seto Y , Wang Y , Wakatake T , Sakakibara H , Demura T , Yamaguchi S , Yoneyama K , Manabe RI , Nelson DC , Schulman AH , Timko MP , dePamphilis CW , Choi D , Shirasu K
Ref : Current Biology , 29 :3041 , 2019
Abstract : Parasitic plants in the genus Striga, commonly known as witchweeds, cause major crop losses in sub-Saharan Africa and pose a threat to agriculture worldwide. An understanding of Striga parasite biology, which could lead to agricultural solutions, has been hampered by the lack of genome information. Here, we report the draft genome sequence of Striga asiatica with 34,577 predicted protein-coding genes, which reflects gene family contractions and expansions that are consistent with a three-phase model of parasitic plant genome evolution. Striga seeds germinate in response to host-derived strigolactones (SLs) and then develop a specialized penetration structure, the haustorium, to invade the host root. A family of SL receptors has undergone a striking expansion, suggesting a molecular basis for the evolution of broad host range among Striga spp. We found that genes involved in lateral root development in non-parasitic model species are coordinately induced during haustorium development in Striga, suggesting a pathway that was partly co-opted during the evolution of the haustorium. In addition, we found evidence for horizontal transfer of host genes as well as retrotransposons, indicating gene flow to S. asiatica from hosts. Our results provide valuable insights into the evolution of parasitism and a key resource for the future development of Striga control strategies.
ESTHER : Yoshida_2019_Curr.Biol_29_3041
PubMedSearch : Yoshida_2019_Curr.Biol_29_3041
PubMedID: 31522940
Gene_locus related to this paper: straf-a0a5a7qxe3

Title : Terminalia chebula extract prevents scopolamine-induced amnesia via cholinergic modulation and anti-oxidative effects in mice - Kim_2018_BMC.Complement.Altern.Med_18_136
Author(s) : Kim MS , Lee DY , Lee J , Kim HW , Sung SH , Han JS , Jeon WK
Ref : BMC Complement Altern Med , 18 :136 , 2018
Abstract : BACKGROUND: Terminalia chebula Retz. (Combretaceae) is a traditional herbal medicine that is widely used in the treatment of diabetes, immunodeficiency diseases, and stomach ulcer in Asia. However, the anti-amnesic effect of T. chebula has not yet been investigated. The present study was designed to determine whether T. chebula extract (TCE) alleviates amnesia induced by scopolamine in mice. We also investigated possible mechanisms associated with cholinergic system and anti-oxidant effects. METHODS: TCE (100 or 200 mg/kg) was orally administered to mice for fourteen days (days 1-14), and scopolamine was intraperitoneally injected to induce memory impairment for seven days (days 8-14). Learning and memory status were evaluated using the Morris water maze. Hippocampal levels of acetylcholine (ACh), acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) were measured ex vivo. Levels of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA) in the hippocampus were also examined. RESULTS: In the Morris water maze task, TCE treatment reversed scopolamine-induced learning and memory deficits in acquisition and retention. TCE reduced hippocampal AChE activities and increased ChAT and ACh levels in the scopolamine-induced model. Moreover, TCE treatment suppressed scopolamine-induced oxidative damage by ameliorating the increased levels of ROS, NO, and MDA. CONCLUSION: These findings suggest that TCE exerts potent anti-amnesic effects via cholinergic modulation and anti-oxidant activity, thus providing evidence for its potential as a cognitive enhancer for amnesia.
ESTHER : Kim_2018_BMC.Complement.Altern.Med_18_136
PubMedSearch : Kim_2018_BMC.Complement.Altern.Med_18_136
PubMedID: 29716575

Title : New reference genome sequences of hot pepper reveal the massive evolution of plant disease-resistance genes by retroduplication - Kim_2017_Genome.Biol_18_210
Author(s) : Kim S , Park J , Yeom SI , Kim YM , Seo E , Kim KT , Kim MS , Lee JM , Cheong K , Shin HS , Kim SB , Han K , Lee J , Park M , Lee HA , Lee HY , Lee Y , Oh S , Lee JH , Choi E , Lee SE , Jeon J , Kim H , Choi G , Song H , Lee SC , Kwon JK , Koo N , Hong Y , Kim RW , Kang WH , Huh JH , Kang BC , Yang TJ , Lee YH , Bennetzen JL , Choi D
Ref : Genome Biol , 18 :210 , 2017
Abstract : BACKGROUND: Transposable elements are major evolutionary forces which can cause new genome structure and species diversification. The role of transposable elements in the expansion of nucleotide-binding and leucine-rich-repeat proteins (NLRs), the major disease-resistance gene families, has been unexplored in plants. RESULTS: We report two high-quality de novo genomes (Capsicum baccatum and C. chinense) and an improved reference genome (C. annuum) for peppers. Dynamic genome rearrangements involving translocations among chromosomes 3, 5, and 9 were detected in comparison between C. baccatum and the two other peppers. The amplification of athila LTR-retrotransposons, members of the gypsy superfamily, led to genome expansion in C. baccatum. In-depth genome-wide comparison of genes and repeats unveiled that the copy numbers of NLRs were greatly increased by LTR-retrotransposon-mediated retroduplication. Moreover, retroduplicated NLRs are abundant across the angiosperms and, in most cases, are lineage-specific. CONCLUSIONS: Our study reveals that retroduplication has played key roles for the massive emergence of NLR genes including functional disease-resistance genes in pepper plants.
ESTHER : Kim_2017_Genome.Biol_18_210
PubMedSearch : Kim_2017_Genome.Biol_18_210
PubMedID: 29089032
Gene_locus related to this paper: capch-q75qh4 , capan-a0a1u8fuf5 , capan-a0a1u8gmz3 , capch-a0a2g3bqp0 , capba-a0a2g2vcw4 , capan-a0a1u8flz5 , capch-a0a2g3bau3 , capch-a0a2g3b6c0 , capan-a0a2g2y016 , capch-a0a2g3cje8 , capba-a0a2g2xr67 , capan-a0a1u8fpc9 , capan-a0a1u8fqs3 , capan-a0a1u8ft99 , capan-a0a2g2xtt0 , capan-a0a1u8eu02 , capan-a0a1u8hd13 , capan-a0a2g2y0b6

Title : Ginkgo biloba L. extract protects against chronic cerebral hypoperfusion by modulating neuroinflammation and the cholinergic system - Kim_2016_Phytomedicine_23_1356
Author(s) : Kim MS , Bang JH , Lee J , Han JS , Baik TG , Jeon WK
Ref : Phytomedicine , 23 :1356 , 2016
Abstract : BACKGROUND: Ginkgo biloba extract (GBE)-a widely used nutraceutical-is reported to have diverse functions, including positive effects on memory and vasodilatory properties. Although numerous studies have assessed the neuroprotective properties of GBE in ischemia, only a few studies have investigated the neuro-pharmacological mechanisms of action of GBE in chronic cerebral hypoperfusion (CCH). PURPOSE: In the present study, we sought to determine the effects of GBE on CCH-induced neuroinflammation and cholinergic dysfunction in a rat model of bilateral common carotid artery occlusion (BCCAo).
METHODS: Chronic BCCAo was induced in adult male Wistar rats to reflect the CCH conditions. On day 21 after BCCAo, the animals were treated orally with saline or GBE (5, 10, 20, and 40mg/kg) daily for 42 days. After the final treatment, brain tissues were isolated for the immunohistochemical analysis of glial markers and choline acetyltransferase (ChAT), as well as for the western blot analysis of proinflammatory cytokines, toll-like receptor (TLR)-related pathway, receptor for advanced glycation end products (RAGE), angiotensin-II (Ang-II), and phosphorylated mitogen-activated protein kinases (MAPKs).
RESULTS: BCCAo increased glial proliferation in the hippocampus and white matter, whereas proliferation was significantly attenuated by GBE treatment. GBE also attenuated the BCCAo-related increases in the hippocampal expression of proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6), TLR4, myeloid differentiation primary response gene 88, RAGE, Ang-II, and phosphorylated MAPKs (ERK, p38, and JNK). Furthermore, GBE treatment restored the ChAT expression in the basal forebrain following BCCAo.
CONCLUSIONS: These findings suggest that GBE has specific neuroprotective effects that may be useful for the treatment of CCH. The pharmacological mechanism of GBE partly involves the modulation of inflammatory mediators and the cholinergic system.
ESTHER : Kim_2016_Phytomedicine_23_1356
PubMedSearch : Kim_2016_Phytomedicine_23_1356
PubMedID: 27765355

Title : Ameliorating Effects of Ethanol Extract of Fructus mume on Scopolamine-Induced Memory Impairment in Mice - Kim_2015_Evid.Based.Complement.Alternat.Med_2015_102734
Author(s) : Kim MS , Jeon WK , Lee KW , Park YH , Han JS
Ref : Evid Based Complement Alternat Med , 2015 :102734 , 2015
Abstract : We previously reported that Fructus mume (F. mume) extract shows protective effects on memory impairments and anti-inflammatory effects induced by chronic cerebral hypoperfusion. Neurodegeneration of basal cholinergic neurons is also observed in the brain with chronic cerebral hypoperfusion. Therefore, the present study was conducted to examine whether F. mume extracts enhance cognitive function via the action of cholinergic neuron using a scopolamine-induced animal model of memory impairments. F. mume (50, 100, or 200 mg/kg) was administered to C57BL/6 mice for 14 days (days 1-14) and memory impairment was induced by scopolamine (1 mg/kg), a muscarinic receptor antagonist for 7 days (days 8-14). Spatial memory was assessed using Morris water maze and hippocampal level of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) was examined by ELISA and immunoblotting. Mice that received scopolamine alone showed impairments in acquisition and retention in Morris water maze task and increased activity of AChE in the hippocampus. Mice that received F. mume and scopolamine showed no scopolamine-induced memory impairment and increased activity of AChE. In addition, treatments of F. mume increased ChAT expression in the hippocampus. These results indicated that F. mume might enhance cognitive function via action of cholinergic neurons.
ESTHER : Kim_2015_Evid.Based.Complement.Alternat.Med_2015_102734
PubMedSearch : Kim_2015_Evid.Based.Complement.Alternat.Med_2015_102734
PubMedID: 25705233

Title : Anithiactins A-C, modified 2-phenylthiazoles from a mudflat-derived Streptomyces sp - Kim_2014_J.Nat.Prod_77_2716
Author(s) : Kim H , Yang I , Patil RS , Kang S , Lee J , Choi H , Kim MS , Nam SJ , Kang H
Ref : Journal of Natural Products , 77 :2716 , 2014
Abstract : Intensive investigation of the chemical components of a Streptomyces sp. isolated from mudflat sediments collected on the southern coast of the Korean peninsula led to the isolation of three new compounds, anithiactins A-C (1-3). The chemical structures of anithiactins A and C were determined by interpretation of NMR data analyses, while the chemical structure of anithiactin B was established from a combination of NMR spectroscopic and crystallographic data analyses. The structure of anithiactin A was also confirmed by total synthesis. These three anithiactins displayed moderate acetylcholinesterase inhibitory activity with no significant cytotoxicity.
ESTHER : Kim_2014_J.Nat.Prod_77_2716
PubMedSearch : Kim_2014_J.Nat.Prod_77_2716
PubMedID: 25455147

Title : Discovery of beta-aminoacyl containing thiazolidine derivatives as potent and selective dipeptidyl peptidase IV inhibitors - Park_2011_Bioorg.Med.Chem.Lett_21_1366
Author(s) : Park WS , Kang SK , Jun MA , Shin MS , Kim KY , Rhee SD , Bae MA , Kim MS , Kim KR , Kang NS , Yoo SE , Lee JO , Song DH , Silinski P , Schneider SE , Ahn JH , Kim SS
Ref : Bioorganic & Medicinal Chemistry Lett , 21 :1366 , 2011
Abstract : A series of beta-aminoacyl containing thiazolidine derivatives was synthesized and evaluated for their ability to inhibit DPP-IV. Several thiazolidine derivatives with an acid moiety were found to be potent DPP-IV inhibitors. Among them, compound 2da is the most active in this series with an IC(50) value of 1 nM, and it showed excellent selectivity over DPP-IV related enzymes including DPP-2, DPP-8, and DPP-9. Compound 2da is chemically and metabolically stable, and showed no CYP inhibition, hERG binding or cytotoxicity. Compound 2db, an ester prodrug of 2da, showed good in vivo DPP-IV inhibition after oral administration in rat and dog models.
ESTHER : Park_2011_Bioorg.Med.Chem.Lett_21_1366
PubMedSearch : Park_2011_Bioorg.Med.Chem.Lett_21_1366
PubMedID: 21306895
Gene_locus related to this paper: human-DPP4

Title : Severity of diabetes governs vascular lipoprotein lipase by affecting enzyme dimerization and disassembly - Wang_2011_Diabetes_60_2041
Author(s) : Wang Y , Puthanveetil P , Wang F , Kim MS , Abrahani A , Rodrigues B
Ref : Diabetes , 60 :2041 , 2011
Abstract : OBJECTIVE: In diabetes, when glucose consumption is restricted, the heart adapts to use fatty acid (FA) exclusively. The majority of FA provided to the heart comes from the breakdown of circulating triglyceride (TG), a process catalyzed by lipoprotein lipase (LPL) located at the vascular lumen. The objective of the current study was to determine the mechanisms behind LPL processing and breakdown after moderate and severe diabetes. RESEARCH DESIGN AND METHODS: To induce acute hyperglycemia, diazoxide, a selective, ATP-sensitive K(+) channel opener was used. For chronic diabetes, streptozotocin, a beta-cell-specific toxin was administered at doses of 55 or 100 mg/kg to generate moderate and severe diabetes, respectively. Cardiac LPL processing into active dimers and breakdown at the vascular lumen was investigated. RESULTS: After acute hyperglycemia and moderate diabetes, more LPL is processed into an active dimeric form, which involves the endoplasmic reticulum chaperone calnexin. Severe diabetes results in increased conversion of LPL into inactive monomers at the vascular lumen, a process mediated by FA-induced expression of angiopoietin-like protein 4 (Angptl-4). CONCLUSIONS: In acute hyperglycemia and moderate diabetes, exaggerated LPL processing to dimeric, catalytically active enzyme increases coronary LPL, delivering more FA to the heart when glucose utilization is compromised. In severe chronic diabetes, to avoid lipid oversupply, FA-induced expression of Angptl-4 leads to conversion of LPL to inactive monomers at the coronary lumen to impede TG hydrolysis. Results from this study advance our understanding of how diabetes changes coronary LPL, which could contribute to cardiovascular complications seen with this disease.
ESTHER : Wang_2011_Diabetes_60_2041
PubMedSearch : Wang_2011_Diabetes_60_2041
PubMedID: 21646389

Title : In vitro metabolism and transport of the new dipeptidyl peptidase 4 inhibitors, KR66222 and KR66223 - Ahn_2011_Xenobiotica_41_445
Author(s) : Ahn HJ , Kim KB , Liu KH , Shin JG , Ahn JH , Kim MS , Bae MA , Song IS
Ref : Xenobiotica , 41 :445 , 2011
Abstract : We investigated the in vitro metabolism and transport of KR66222 and KR66223, new inhibitors of dipeptidyl peptidase (DPP) 4, using human liver microsomes (HLMs) and a Caco-2 cell monolayer. Human liver microsomal incubation of KR66222 in the presence of the NADPH-generating system resulted in the formation of two metabolites, identified as S-oxidation (KR68334) and hydrolysis (KR66223) products using liquid chromatography/tandem mass spectrometry. The formation of KR66223 via an esterase and the formation of KR68334 via CYP3A5 and CYP3A4 seem to be major factors in the in vitro metabolism of KR66222 using HLMs. Additionally, KR66222 had a significantly greater basal to apical transport rate (2.5-fold) than apical to basal transport in the Caco-2 cell monolayer, suggesting the involvement of an efflux transport system. Further studies using inhibitors of efflux transporters and P-glycoprotein (P-gp) overexpressed cells revealed that P-gp was involved in the basal to apical transport of KR66222. These findings suggest that KR66222 undergoes a significant first pass effect, which may serve to decrease the bioavailability of KR66222. The active metabolite, KR66223, was stable for 1 h at 37 degrees C in pooled HLMs (98.9 +/- 2.6% of control) and did not undergo P-gp-mediated efflux in Caco-2 cells. Apparent permeability of KR66223 (4.96 x 10(-6) cm/s) was comparable to that of KR66222 (4.08 x 10(-6) cm/s). In conclusion, considering pharmacokinetic variability and the intestinal first-pass effect caused by the involvement of CYP3A and P-gp, KR66223 seems to have better in vitro metabolism and permeability characteristics than KR66222.
ESTHER : Ahn_2011_Xenobiotica_41_445
PubMedSearch : Ahn_2011_Xenobiotica_41_445
PubMedID: 21341986

Title : Fustin flavonoid attenuates beta-amyloid (1-42)-induced learning impairment - Jin_2009_J.Neurosci.Res_87_3658
Author(s) : Jin CH , Shin EJ , Park JB , Jang CG , Li Z , Kim MS , Koo KH , Yoon HJ , Park SJ , Choi WC , Yamada K , Nabeshima T , Kim HC
Ref : Journal of Neuroscience Research , 87 :3658 , 2009
Abstract : Natural flavonoids ameliorate amyloid-beta peptide (Abeta)-induced neurotoxicity. We examined whether the fustin flavonoid affects Abeta-induced learning impairment in mice. Repeated treatment with fustin significantly attenuated Abeta (1-42)-induced conditioned fear and passive avoidance behaviors. This effect was comparable to that of EGb761, a standard extract of ginkgo. Fustin treatment significantly prevented decreases in acetylcholine (ACh) levels, choline acetyltransferase (ChAT) activity, and ChAT gene expression induced by Abeta (1-42). Fustin also consistently suppressed increases in acetyl cholinesterase (AChE) activity and AChE gene expression induced by Abeta (1-42). In addition, fustin significantly attenuated Abeta (1-42)-induced selective decreases in muscarinic M1 receptor gene expression and muscarinic M1 receptor binding activity (as determined by [(3)H]pirenzepine binding) by modulating extracellular signal-regulated kinase 1/2 (ERK 1/2) and cAMP response-element binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) expression. These effects of fustin were reversed by treatment with dicyclomine, a muscarinic M1 receptor antagonist, and SL327, a selective ERK inhibitor, but not by chelerythrine, a pan-protein kinase C (PKC) inhibitor. Taken together, our results suggest that fustin attenuates Abeta (1-42)-impaired learning, and that the ERK/CREB/BDNF pathway is important for the M1 receptor-mediated cognition-enhancing effects of fustin.
ESTHER : Jin_2009_J.Neurosci.Res_87_3658
PubMedSearch : Jin_2009_J.Neurosci.Res_87_3658
PubMedID: 19533734

Title : Complete genome sequence of Rhodobacter sphaeroides KD131 - Lim_2009_J.Bacteriol_191_1118
Author(s) : Lim SK , Kim SJ , Cha SH , Oh YK , Rhee HJ , Kim MS , Lee JK
Ref : Journal of Bacteriology , 191 :1118 , 2009
Abstract : Rhodobacter sphaeroides is a purple nonsulfur photosynthetic bacterium that is considered a possible source of H(2) production. R. sphaeroides KD131, which was isolated from sea mud in South Korea, was found to produce high levels of H(2). Here we report the complete and annotated genome sequence of R. sphaeroides KD131.
ESTHER : Lim_2009_J.Bacteriol_191_1118
PubMedSearch : Lim_2009_J.Bacteriol_191_1118
PubMedID: 19028901
Gene_locus related to this paper: rhos1-a3ph69 , rhos4-q3ixk0 , rhos4-q3iye8 , rhos4-q3iym6 , rhos4-q3j3q4 , rhos4-q3j204 , rhos4-q3j479 , rhos4-q3j480 , rhosh-BchO , rhosh-q1l7n7 , rhosk-b9kl36 , rhosk-b9kmj1 , rhosk-b9kqs4

Title : Cleavage of protein kinase D after acute hypoinsulinemia prevents excessive lipoprotein lipase-mediated cardiac triglyceride accumulation - Kim_2009_Diabetes_58_2464
Author(s) : Kim MS , Wang F , Puthanveetil P , Kewalramani G , Innis S , Marzban L , Steinberg SF , Webber TD , Kieffer TJ , Abrahani A , Rodrigues B
Ref : Diabetes , 58 :2464 , 2009
Abstract : OBJECTIVE: During hypoinsulinemia, when cardiac glucose utilization is impaired, the heart rapidly adapts to using more fatty acids. One means by which this is achieved is through lipoprotein lipase (LPL). We determined the mechanisms by which the heart regulates LPL after acute hypoinsulinemia. RESEARCH DESIGN AND METHODS: We used two different doses of streptozocin (55 [D-55] and 100 [D-100] mg/kg) to induce moderate and severe hypoinsulinemia, respectively, in rats. Isolated cardiomyocytes were also used for transfection or silencing of protein kinase D (PKD) and caspase-3. RESULTS: There was substantial increase in LPL in D-55 hearts, an effect that was absent in severely hypoinsulinemic D-100 animals. Measurement of PKD, a key element involved in increasing LPL, revealed that only D-100 hearts showed an increase in proteolysis of PKD, an effect that required activation of caspase-3 together with loss of 14-3-3zeta, a binding protein that protects enzymes against degradation. In vitro, phosphomimetic PKD colocalized with LPL in the trans-golgi. PKD, when mutated to prevent its cleavage by caspase-3 and silencing of caspase-3, was able to increase LPL activity. Using a caspase inhibitor (Z-DEVD) in D-100 animals, we effectively lowered caspase-3 activity, prevented PKD cleavage, and increased LPL vesicle formation and translocation to the vascular lumen. This increase in cardiac luminal LPL was associated with a striking accumulation of cardiac triglyceride in Z-DEVD-treated D-100 rats. CONCLUSIONS After severe hypoinsulinemia, activation of caspase-3 can restrict LPL translocation to the vascular lumen. When caspase-3 is inhibited, this compensatory response is lost, leading to lipid accumulation in the heart.
ESTHER : Kim_2009_Diabetes_58_2464
PubMedSearch : Kim_2009_Diabetes_58_2464
PubMedID: 19875622

Title : Acute dexamethasone-induced increase in cardiac lipoprotein lipase requires activation of both Akt and stress kinases - Kewalramani_2008_Am.J.Physiol.Endocrinol.Metab_295_E137
Author(s) : Kewalramani G , Puthanveetil P , Kim MS , Wang F , Lee V , Hau N , Beheshti E , Ng N , Abrahani A , Rodrigues B
Ref : American Journal of Physiology Endocrinol Metab , 295 :E137 , 2008
Abstract : Following dexamethasone (DEX), cardiac energy generation is mainly through utilization of fatty acids (FA), with DEX animals demonstrating an increase in coronary lipoprotein lipase (LPL), an enzyme that hydrolyzes lipoproteins to FA. We examined the mechanisms by which DEX augments cardiac LPL. DEX was injected in rats, and hearts were removed, or isolated cardiomyocytes were incubated with DEX (0-8 h), for measurement of LPL activity and Western blotting. Acute DEX induced whole body insulin resistance, likely an outcome of a decrease in insulin signaling in skeletal muscle, but not cardiac tissue. The increase in luminal LPL activity after DEX was preceded by rapid nongenomic alterations, which included phosphorylation of AMPK and p38 MAPK, that led to phosphorylation of heat shock protein (HSP)25 and actin cytoskeleton rearrangement, facilitating LPL translocation to the myocyte cell surface. Unlike its effects in vivo, although DEX activated AMPK and p38 MAPK in cardiomyocytes, there was no phosphorylation of HSP25, nor was there any evidence of F-actin polymerization or an augmentation of LPL activity up to 8 h after DEX. Combining DEX with insulin appreciably enhanced cardiomyocyte LPL activity, which closely mirrored a robust elevation in phosphorylation of HSP25 and F-actin polymerization. Silencing of p38 MAPK, inhibition of PI 3-kinase, or preincubation with cytochalasin D prevented the increases in LPL activity. Our data suggest that, following DEX, it is a novel, rapid, nongenomic phosphorylation of stress kinases that, together with insulin, facilitates LPL translocation to the myocyte cell surface.
ESTHER : Kewalramani_2008_Am.J.Physiol.Endocrinol.Metab_295_E137
PubMedSearch : Kewalramani_2008_Am.J.Physiol.Endocrinol.Metab_295_E137
PubMedID: 18460599

Title : Acute diabetes moderates trafficking of cardiac lipoprotein lipase through p38 mitogen-activated protein kinase-dependent actin cytoskeleton organization - Kim_2008_Diabetes_57_64
Author(s) : Kim MS , Kewalramani G , Puthanveetil P , Lee V , Kumar U , An D , Abrahani A , Rodrigues B
Ref : Diabetes , 57 :64 , 2008
Abstract : OBJECTIVE: Heart disease is a leading cause of death in diabetes and could occur because of excessive use of fatty acid for energy generation. Our objective was to determine the mechanisms by which AMP-activated protein kinase (AMPK) augments cardiac lipoprotein lipase (LPL), the enzyme that provides the heart with the majority of its fatty acid. RESEARCH DESIGN AND
METHODS: We used diazoxide in rats to induce hyperglycemia or used 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and thrombin to directly stimulate AMPK and p38 mitogen-activated protein kinase (MAPK), respectively, in cardiomyocytes.
RESULTS: There was a substantial increase in LPL at the coronary lumen following 4 h of diazoxide. In these diabetic animals, phosphorylation of AMPK, p38 MAPK, and heat shock protein (Hsp)25 produced actin cytoskeleton rearrangement to facilitate LPL translocation to the myocyte surface and, eventually, the vascular lumen. AICAR activated AMPK, p38 MAPK, and Hsp25 in a pattern similar to that seen with diabetes. AICAR also appreciably enhanced LPL, an effect reduced by preincubation with the p38 MAPK inhibitor SB202190 or by cytochalasin D, which inhibits actin polymerization. Thrombin activated p38 MAPK in the absence of AMPK phosphorylation. Comparable with diabetes, activation of p38 MAPK and, subsequently, Hsp25 phosphorylation and F-actin polymerization corresponded with an enhanced LPL activity. SB202190 and silencing of p38 MAPK also prevented these effects induced by thrombin and AICAR, respectively.
CONCLUSIONS: We propose that AMPK recruitment of LPL to the cardiomyocyte surface (which embraces p38 MAPK activation and actin cytoskeleton polymerization) represents an immediate compensatory response by the heart to guarantee fatty acid supply when glucose utilization is compromised.
ESTHER : Kim_2008_Diabetes_57_64
PubMedSearch : Kim_2008_Diabetes_57_64
PubMedID: 17942824

Title : Protein kinase D is a key regulator of cardiomyocyte lipoprotein lipase secretion after diabetes - Kim_2008_Circ.Res_103_252
Author(s) : Kim MS , Wang F , Puthanveetil P , Kewalramani G , Hosseini-Beheshti E , Ng N , Wang Y , Kumar U , Innis S , Proud CG , Abrahani A , Rodrigues B
Ref : Circulation Research , 103 :252 , 2008
Abstract : The diabetic heart switches to exclusively using fatty acid (FA) for energy supply and does so by multiple mechanisms including hydrolysis of lipoproteins by lipoprotein lipase (LPL) positioned at the vascular lumen. We determined the mechanism that leads to an increase in LPL after diabetes. Diazoxide (DZ), an agent that decreases insulin secretion and causes hyperglycemia, induced a substantial increase in LPL activity at the vascular lumen. This increase in LPL paralleled a robust phosphorylation of Hsp25, decreasing its association with PKCdelta, allowing this protein kinase to phosphorylate and activate protein kinase D (PKD), an important kinase that regulates fission of vesicles from the golgi membrane. Rottlerin, a PKCdelta inhibitor, prevented PKD phosphorylation and the subsequent increase in LPL. Incubating control myocytes with high glucose and palmitic acid (Glu+PA) also increased the phosphorylation of Hsp25, PKCdelta, and PKD in a pattern similar to that seen with diabetes, in addition to augmenting LPL activity. In myocytes in which PKD was silenced or a mutant form of PKCdelta was expressed, high Glu+PA were incapable of increasing LPL. Moreover, silencing of cardiomyocyte Hsp25 allowed phorbol 12-myristate 13-acetate to elicit a significant phosphorylation of PKCdelta, an appreciable association between PKCdelta and PKD, and a vigorous activation of PKD. As these cells also demonstrated an additional increase in LPL, our data imply that after diabetes, PKD control of LPL requires dissociation of Hsp25 from PKCdelta, association between PKCdelta and PKD, and vesicle fission. Results from this study could help in restricting cardiac LPL translocation, leading to strategies that overcome contractile dysfunction after diabetes.
ESTHER : Kim_2008_Circ.Res_103_252
PubMedSearch : Kim_2008_Circ.Res_103_252
PubMedID: 18583709

Title : Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host - Khovidhunkit_2004_J.Lipid.Res_45_1169
Author(s) : Khovidhunkit W , Kim MS , Memon RA , Shigenaga JK , Moser AH , Feingold KR , Grunfeld C
Ref : J Lipid Res , 45 :1169 , 2004
Abstract : Infection and inflammation induce the acute-phase response (APR), leading to multiple alterations in lipid and lipoprotein metabolism. Plasma triglyceride levels increase from increased VLDL secretion as a result of adipose tissue lipolysis, increased de novo hepatic fatty acid synthesis, and suppression of fatty acid oxidation. With more severe infection, VLDL clearance decreases secondary to decreased lipoprotein lipase and apolipoprotein E in VLDL. In rodents, hypercholesterolemia occurs attributable to increased hepatic cholesterol synthesis and decreased LDL clearance, conversion of cholesterol to bile acids, and secretion of cholesterol into the bile. Marked alterations in proteins important in HDL metabolism lead to decreased reverse cholesterol transport and increased cholesterol delivery to immune cells. Oxidation of LDL and VLDL increases, whereas HDL becomes a proinflammatory molecule. Lipoproteins become enriched in ceramide, glucosylceramide, and sphingomyelin, enhancing uptake by macrophages. Thus, many of the changes in lipoproteins are proatherogenic. The molecular mechanisms underlying the decrease in many of the proteins during the APR involve coordinated decreases in several nuclear hormone receptors, including peroxisome proliferator-activated receptor, liver X receptor, farnesoid X receptor, and retinoid X receptor. APR-induced alterations initially protect the host from the harmful effects of bacteria, viruses, and parasites. However, if prolonged, these changes in the structure and function of lipoproteins will contribute to atherogenesis.
ESTHER : Khovidhunkit_2004_J.Lipid.Res_45_1169
PubMedSearch : Khovidhunkit_2004_J.Lipid.Res_45_1169
PubMedID: 15102878

Title : Enhanced expression of microsomal epoxide hydrolase and glutathione S-transferase by imidazole correlates with the radioprotective effect - Lee_2000_Res.Commun.Mol.Pathol.Pharmacol_108_155
Author(s) : Lee AK , Cho CK , Kim MS , Kim SG
Ref : Res Commun Mol Pathol Pharmacol , 108 :155 , 2000
Abstract : Previous studies have shown that induction of microsomal epoxide hydrolase (mEH) and glutathione S-transferase (GST) by oltipraz correlated with the radioprotective effect. The present study was designed to investigate the expression of the antioxidant enzymes and the radioprotective effect by imidazole (IM). Northern blot analysis revealed that IM increased the mEH and GST mRNA levels in the rat liver in a dose-dependent manner. Rats irradiated with 3 Gy of gamma-rays in combination with IM showed enhanced increases in mEH and rGSTA2 mRNAs, as compared to either IM or irradiation alone. IM prevented elevations in the hepatic GSH content by gamma-irradiation. In contrast to IM, cysteine blocked radiation-inducible increases in the mRNAs with no suppression of the GSH content. The radioprotective effect by IM was greater than that by cysteine, as assessed by the 30-day survival rate of mice (i.e. 80% and 69%, respectively, vs. 48% in control). These results demonstrated that IM enhanced radiation-inducible mEH and GST expression with prevention of the increase in GSH content, which correlated with the radioprotective effect, and that the mechanistic basis of radioprotection by IM differed from that by cysteine.
ESTHER : Lee_2000_Res.Commun.Mol.Pathol.Pharmacol_108_155
PubMedSearch : Lee_2000_Res.Commun.Mol.Pathol.Pharmacol_108_155
PubMedID: 11913708