Korean BioInformation Center

Daejeon, South Korea

Korean BioInformation Center

Daejeon, South Korea
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Jung H.A.,Chonbuk National University | Moon H.E.,Pukyong National University | Oh S.H.,Korean BioInformation Center | Kim B.-W.,Korea University | And 3 more authors.
Chemico-Biological Interactions | Year: 2012

Aldose reductase inhibitors (ARIs) suppressing the hyperglycemia-induced polyol pathway have been provided as potential therapeutic candidates in the treatment and prevention of diabetic complications. Based upon structure-activity relationships of desmethylanhydroicaritin (1) and sophoflavescenol (2) as promising ARIs, 3,4′-dihydroxy flavonols with a prenyl or lavandulyl group at the C-8 position and a hydroxyl or methoxy group at the C-5 position are important for aldose reductase (AR) inhibition. In order to prove the above results, a combination of computational prediction and enzyme kinetics has begun to emerge as an effective screening technique for the potential. In the present study, we predicted the 3D structure of AR in rat and human using a docking algorithm to simulate binding between AR and prenylated flavonoids (1 and 2) and kaempferol (3) and scrutinized the reversible inhibition of AR by these ARIs. Docking simulation results of 1-3 demonstrated negative binding energies (Autodock 4.0 = -9.11 to -7.64 kcal/mol; Fred 2.0 = -79.54 to -51.84 kcal/mol) and an additional hydrogen bond through Phe122 and Trp219, in addition to the previously proposed interaction of AR and phenolics through Trp20, Tyr48, His110, and Trp111 residues, indicating that the presence of 8-prenyl and 5-methyl groups might potentiate tighter binding to the active site of the enzyme and more effective AR inhibitors. Moreover, types of AR inhibition were different depending on the presence or absence of the 8-prenyl group, in that 1 and 2 are mixed inhibitors with respective K i values of 0.69 μM and 0.94 μM, while 3 showed noncompetitive inhibition with a K i value of 4.65 μM. The present study suggests that an effective strategy for screening potential ARIs could be established by predicting 3D structural conformation of prenylated flavonoids and the orientation within the enzyme as well as by simultaneously determining the mode of enzyme inhibition. © 2012 Elsevier Ireland Ltd. All rights reserved.


Jung H.A.,Chonbuk National University | Islam M.N.,Pukyong National University | Lee C.M.,Pukyong National University | Oh S.H.,Korean BioInformation Center | And 4 more authors.
Chemico-Biological Interactions | Year: 2013

In the present study, we investigated the anti-diabetic potential of fucosterol by evaluating the ability of this compound to inhibit rat lens aldose reductase (RLAR), human recombinant aldose reductase (HRAR), protein tyrosine phosphatase 1B (PTP1B), and α-glucosidase. Fucosterol displayed moderate inhibitory activity against RLAR, HRAR, and PTP1B. However, it showed weak or no activity against AGE formation and α-glucosidase. In addition, our kinetic study revealed that fucosterol showed a mixed type inhibition against RLAR and HRAR, while it noncompetitively inhibited PTP1B. Since fucosterol inhibited aldose reductase (AR), it holds great promise for use in the treatment of diabetic complications. Therefore, we predicted the 3D structure of AR in rat and human using the Autodock program to simulate binding between AR and fucosterol and evaluate the binding site-directed inhibition of AR by fucosterol. Results of the docking simulations of fucosterol demonstrated negative binding energies (-8.2 kcal/mol for RLAR and -8.5 kcal/mol for HRAR), which indicated a higher affinity and tighter binding capacity of fucosterol for the active site of the enzyme. In particular, the hydrophobic ring system and the aliphatic side chain of fucosterol were found to be tightly bound in a specificity pocket through apolar amino acid residues on AR, while the anion binding site on AR interacts with the 3-hydroxyl group and the double bond on the side chain of fucosterol. The results of the present study clearly demonstrated the potential of using fucosterol for the management and treatment of diabetes and diabetes-associated complications. © 2013 Elsevier Ireland Ltd. All rights reserved.


Kim S.-J.,University of Ulsan | Lee T.H.,University of Ulsan | Nam S.H.,University of Ulsan | Kim J.-H.,University of Ulsan | And 5 more authors.
Journal of the National Cancer Institute | Year: 2017

Background: The UBA6-specific E2 conjugating enzyme 1 (USE1) ubiquitin enzyme cascade is a poorly characterized arm of the ubiquitin-proteasome system. We investigated whether the UBA6-USE1 enzyme cascade plays a role in lung cancer tumorigenesis. Methods: USE1 expression was assessed in tumor-normal paired samples from 106 lung cancer patients by immunoblot. USE1 was stably overexpressed and knocked down in lung cancer cell lines to evaluate cell proliferation, colony formation, and invasion. Xenograft models were used to determine the effects of USE1 on tumor growth (n=7). Proteomics analysis was used to identify proteins interacting with USE1. The USE1 gene was sequenced in lung cancer patients, and missense mutations of USE1 were generated to evaluate its function. All statistical tests were two-sided. Results: USE1 proteins were frequently overexpressed in lung cancer patients (92.5%) Stable overexpression of USE1 increased cell proliferation (P =.002), migration (P < .001), and invasion (P < .001), whereas knockdown of USE1 reduced cell proliferation (P < .001), migration (P =.003), and invasion in lung cancer cells and xenograft models (P < .001). USE1 was found to have a conserved D-box domain, and the level of the protein was regulated by the anaphase-promoting complex. Several missense mutations in USE1 identified in patients prolong the stability of the protein. Conclusions: USE1 proteins are frequently overexpressed in lung cancer, and missense mutations in USE1 prolong the halflife of the protein, promoting tumor formation. Our findings reveal novel roles for USE1 in lung cancer and the possible use of USE1 as a novel biomarker and therapeutic target for lung cancer treatment. © The Author 2017.


PubMed | Pukyong National University, Kyungpook National University, Korean BioInformation Center, Catholic University of Daegu and iMinh City University of Medicine and Pharmacy
Type: | Journal: Chemico-biological interactions | Year: 2015

Acetylcholinesterase (AChE) inhibitors increase the availability of acetylcholine in central cholinergic synapses and are the most promising drugs currently available for the treatment of Alzheimers disease (AD). Our screening study indicated that the water fraction of the methanolic extract of Lycopodiella cernua (L.) Pic. Serm. significantly inhibited AChE invitro. Bioassay-guided fractionation led to the isolation of a new lignan glycoside, lycocernuaside A (12), and fourteen known compounds (1-11 and 13-15). Compound 7 exhibited the most potent AChE inhibitory activity with an IC50 value of 0.23M. Compound 15 had the most potent inhibitory activity against BChE and BACE1 with IC50 values of 0.62 and 2.16M, respectively. Compounds 4 and 7 showed mixed- and competitive-type AChE inhibition. Compound 7 noncompetitively inhibited BChE whereas 15 showed competitive and 8, 13, and 14 showed mixed-type inhibition. The docking results for complexes with AChE or BChE revealed that inhibitors 4, 7, and 15 stably positioned themselves in several pocket/catalytic domains of the AChE and BChE residues.


Cho S.,Ewha Womans University | Jun Y.,Ewha Womans University | Lee S.,Ewha Womans University | Choi H.-S.,Ewha Womans University | And 6 more authors.
Nucleic Acids Research | Year: 2011

MiRGator is an integrated database of microRNA (miRNA)-associated gene expression, target prediction, disease association and genomic annotation, which aims to facilitate functional investigation of miRNAs. The recent version of miRGator v2.0 contains information about (i) human miRNA expression profiles under various experimental conditions, (ii) paired expression profiles of both mRNAs and miRNAs, (iii) gene expression profiles under miRNA-perturbation (e.g. miRNA knockout and overexpression), (iv) known/predicted miRNA targets and (v) miRNA-disease associations. In total, >8000 miRNA expression profiles, ̃300 miRNA-perturbed gene expression profiles and ̃2000 mRNA expression profiles are compiled with manually curated annotations on disease, tissue type and perturbation. By integrating these data sets, a series of novel associations (miRNA-miRNA, miRNA-disease and miRNA-target) is extracted via shared features. For example, differentially expressed genes (DEGs) after miRNA knockout were systematically compared against miRNA targets. Likewise, differentially expressed miRNAs (DEmiRs) were compared with disease-associated miRNAs. Additionally, miRNA expression and disease-phenotype profiles revealed miRNA pairs whose expression was regulated in parallel in various experimental and disease conditions. Complex associations are readily accessible using an interactive network visualization interface. The miRGator v2.0 serves as a reference database to investigate miRNA expression and function (http://miRGator.kobic.re.kr). © The Author(s) 2010.


Jung H.A.,Pukyong National University | Oh S.H.,Korean BioInformation Center | Choi J.S.,Pukyong National University | Choi J.S.,Dong - Eui University
Bioorganic and Medicinal Chemistry Letters | Year: 2010

In our consecutive research on an anti-AD remedy derived from maritime plants, the BACE1 inhibitory activities of Eisenia bicyclis and its isolated phlorotannins were evaluated. The E. bicyclis extract and its fractions exhibited predominant BACE1 inhibition. With the exception of phloroglucinol (1), all test phlorotannins isolated from the most active EtOAc soluble fraction, showed significant and non-competitive inhibition against BACE1:dioxinodehydroeckol (2, IC50 = 5.35 μM; Ki = 8.0); eckol (3, IC50 = 12.20 μM; Ki = 13.9); phlorofurofucoeckol-A (4, IC50 = 2.13 μM; Ki = 1.3); dieckol (5, IC50 = 2.21 μM; Ki = 1.5); triphloroethol A (6, IC50 = 11.68 μM; Ki = 12.1); 7-phloroethol (7, IC50 = 8.59 μM; Ki = 7.2). In addition, plausible protein-ligand interactions of 3, 4, and 5 were similar and may occur primarily through the TYR132 and THR133 of BACE1 via molecular docking simulations (autodock 4.0 and fred 2.0 programs). As a result, the E. bicyclis extract and the phlorotannins contained therein would clearly have beneficial use in the development of therapeutic and preventive agents for AD and suggest potential guidelines for the design of BACE-selective inhibitors. © 2010 Elsevier Ltd. All rights reserved.


Choi J.S.,Pukyong National University | Ali M.Y.,Pukyong National University | Jung H.A.,Chonbuk National University | Oh S.H.,Korean BioInformation Center | And 2 more authors.
Journal of Ethnopharmacology | Year: 2015

Ethnopharmacologic relevance: Rhizoma Coptidis (the rhizome of Coptis chinensis Franch) has commonly been used for treatment of diabetes mellitus in traditional Chinese medicine due to its blood sugarlowering properties and therapeutic benefits which highly related to the alkaloids therein. However, a limited number of studies focused on the Coptis alkaloids other than berberine. Materials and methods: In the present study, we investigated the anti-diabetic potential of Coptis alkaloids, including berberine (1), epiberberine (2), magnoflorine (3), and coptisine (4), by evaluating the ability of these compounds to inhibit protein tyrosine phosphatase 1B (PTP1B), and ONOO--mediated protein tyrosine nitration. We scrutinized the potentials of Coptis alkaloids as PTP1B inhibitors via enzyme kinetics and molecular docking simulation. Results: The Coptis alkaloids 1-4 exhibited remarkable inhibitory activities against PTP1B with the IC50 values of 16.43, 24.19, 28.14, and 51.04 μM, respectively, when compared to the positive control ursolic acid. These alkaloids also suppressed ONOO--mediated tyrosine nitration effectively in a dose dependent manner. In addition, our kinetic study using the Lineweaver-Burk and Dixon plots revealed that 1 and 2 showed a mixed-type inhibition against PTP1B, while 3 and 4 noncompetitively inhibited PTP1B. Moreover, molecular docking simulation of these compounds demonstrated negative binding energies (Autodock 4.0=-6.7 to -7.8 kcal/mol; Fred 2.0=-59.4 to -68.2 kcal/mol) and a high proximity to PTP1B residues, including Phe182 and Asp181 in the WPD loop, Cys215 in the active sites and Tyr46, Arg47, Asp48, Val49, Ser216, Ala217, Gly218, Ile219, Gly220, Arg221 and Gln262 in the pocket site, indicating a higher affinity and tighter binding capacity of these alkaloids for the active site of the enzyme. Conclusion: Our results clearly indicate the promising anti-diabetic potential of Coptis alkaloids as inhibitors on PTP1B as well as suppressors of ONOO--mediated protein tyrosine nitration, and thus hold promise as therapeutic agents for the treatment of diabetes and related disease. © 2015 Elsevier Ireland Ltd. All rights reserved.


PubMed | Pukyong National University, Korean BioInformation Center, Chonbuk National University and University of Cambridge
Type: | Journal: Journal of ethnopharmacology | Year: 2015

Rhizoma Coptidis (the rhizome of Coptis chinensis Franch) has commonly been used for treatment of diabetes mellitus in traditional Chinese medicine due to its blood sugar-lowering properties and therapeutic benefits which highly related to the alkaloids therein. However, a limited number of studies focused on the Coptis alkaloids other than berberine.In the present study, we investigated the anti-diabetic potential of Coptis alkaloids, including berberine (1), epiberberine (2), magnoflorine (3), and coptisine (4), by evaluating the ability of these compounds to inhibit protein tyrosine phosphatase 1B (PTP1B), and ONOO(-)-mediated protein tyrosine nitration. We scrutinized the potentials of Coptis alkaloids as PTP1B inhibitors via enzyme kinetics and molecular docking simulation.The Coptis alkaloids 1-4 exhibited remarkable inhibitory activities against PTP1B with the IC50 values of 16.43, 24.19, 28.14, and 51.04 M, respectively, when compared to the positive control ursolic acid. These alkaloids also suppressed ONOO(-)-mediated tyrosine nitration effectively in a dose dependent manner. In addition, our kinetic study using the Lineweaver-Burk and Dixon plots revealed that 1 and 2 showed a mixed-type inhibition against PTP1B, while 3 and 4 noncompetitively inhibited PTP1B. Moreover, molecular docking simulation of these compounds demonstrated negative binding energies (Autodock 4.0=-6.7 to -7.8 kcal/mol; Fred 2.0=-59.4 to -68.2 kcal/mol) and a high proximity to PTP1B residues, including Phe182 and Asp181 in the WPD loop, Cys215 in the active sites and Tyr46, Arg47, Asp48, Val49, Ser216, Ala217, Gly218, Ile219, Gly220, Arg221 and Gln262 in the pocket site, indicating a higher affinity and tighter binding capacity of these alkaloids for the active site of the enzyme.Our results clearly indicate the promising anti-diabetic potential of Coptis alkaloids as inhibitors on PTP1B as well as suppressors of ONOO(-)-mediated protein tyrosine nitration, and thus hold promise as therapeutic agents for the treatment of diabetes and related disease.


PubMed | Korean Bioinformation Center and sookeun@kribb.re.kr.
Type: Journal Article | Journal: Genome announcements | Year: 2015

Bacillus subtilis ATCC 6051a (=KCTC 1028), which is less domesticated than strain 168, is widely used for the secretory expression of industrial enzymes. Herein, we present the complete genome sequence of the Bacillus subtilis strain ATCC 6051a.


PubMed | Pukyong National University, Korean BioInformation Center, Mawlana Bhashani Science and Technology University, Chonbuk National University and University of Cambridge
Type: Journal Article | Journal: Archives of pharmacal research | Year: 2016

Caffeoylquinic acids, flavonoids, and coumarins isolated from Artemisia capillaris have recently emerged as therapeutic candidates for diabetes and diabetic complications; however, there have been very few studies of the anti-diabetic potential of polyacetylenes. In the present study, we investigated the anti-diabetic potential of two polyacetylenes isolated from A. capillaris, namely capillin and capillinol by investigating their ability to inhibit -glucosidase, protein tyrosine phosphatase 1B (PTP1B), and rat lens aldose reductase (RLAR). Capillin displayed potent inhibitory activity against -glucosidase, PTP1B, and RLAR, while capillinol showed moderate inhibitory activity against -glucosidase and PTP1B at the concentrations tested. In addition, a kinetic study revealed that capillin inhibited -glucosidase and RLAR in a noncompetitive manner, while inhibited PTP1B in a mixed-type manner. Capillinol inhibited -glucosidase and PTP1B in a mixed-type manner. Docking simulations of these compounds demonstrated negative binding energies and close proximity to residues in the binding pocket of PTP1B, indicating that these polyacetylenes have a high affinity and tight binding capacity for the active site of the enzyme. Furthermore, capillin dose-dependently inhibited peroxynitrite (ONOO(-))-mediated tyrosine nitration. The results clearly demonstrate the promising potential of capillin and capillinol as therapeutic interventions for the management of diabetes as well as diabetes-associated complications.

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