• Journal of Veterinary Science
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• 제22권6호
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• pp.92.1-92.12
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• 2021

Background: Naringin and its aglycone naringenin are citrus-derived flavonoids with several pharmacological effects. On the other hand, the mechanism for the anti-diabetic effects of naringenin and naringin are controversial and remain to be clarified further. Objective: This study examined the relationship between glucose uptake and AMP-activated protein kinase (AMPK) phosphorylation by naringenin and naringin in high glucose-treated HepG2 cells. Methods: Glucose uptake was measured using the 2-NBDG fluorescent D-glucose analog. The phosphorylation levels of AMPK and GSK3β (Glycogen synthase kinase 3 beta) were observed by Western blotting. Molecular docking analysis was performed to evaluate the binding affinity of naringenin and naringin to the γ-subunit of AMPK. Results: The treatment with naringenin and naringin stimulated glucose uptake regardless of insulin stimulation in high glucose-treated HepG2 cells. Both flavonoids increased glucose uptake by promoting the phosphorylation of AMPK at Thr172 and increased the phosphorylation of GSK3β. Molecular docking analysis showed that both naringenin and naringin bind to the γ-subunit of AMPK with high binding affinities. In particular, naringin showed higher binding affinity than the true modulator, AMP with all three CBS domains (CBS1, 3, and 4) in the γ-subunit of AMPK. Therefore, both naringenin and naringin could be positive modulators of AMPK activation, which enhance glucose uptake regardless of insulin stimulation in high glucose-treated HepG2 cells. Conclusions: The increased phosphorylation of AMPK at Thr172 by naringenin and naringin might enhance glucose uptake regardless of insulin stimulation in high glucose treated HepG2 cells.

• Bulletin of the Korean Chemical Society
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• 제31권8호
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• pp.2147-2150
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• 2010

c-Jun N-terminal kinase 1 (JNK1) is involved in apoptosis, cell differentiation and proliferation. It has been reported that a flavonol, quercetin, induces cell apoptosis and JNK inhibition. In order to understand the interactions of quercetin and JNK1, we performed receptor-oriented pharmacophore based in silico screening and determined a binding model of human JNK1 and quercetin at the ATP binding site of JNK1. 5-OH of A-ring and carbonyl oxygen of C-ring of quercetin participated in hydrogen bonding interactions with backbone of E109 and M111. Additionally, 3'-OH of quercetin formed a hydrogen bond with backbone of I32. One hydrophobic interaction is related on the binding of quercetin to JNK1 with I32, N114, and V158. Based on this model, we conducted a docking study with other 8 flavonols to find possible flavonoids inhibitors of JNK1. We proposed that one flavonols, rhamnetin, can be a potent inhibitor of JNK and 5-OH of A-ring and 3'-OH of B-ring of flavonols are the essential features for JNK1 inhibition.

• Journal of Microbiology and Biotechnology
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• 제28권8호
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• pp.1401-1411
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• 2018

The serine-threonine kinase AKT plays a pivotal role in tumor progression and is frequently overactivated in cancer cells; this protein is therefore a critical therapeutic target for cancer intervention. We aimed to identify small molecule inhibitors of the pleckstrin homology (PH) domain of AKT to disrupt binding of phosphatidylinositol-3,4,5-trisphosphate (PIP3), thereby downregulating AKT activity. Liposome pulldown assays coupled with fluorescence spectrometry were used to screen flavonoids for inhibition of the AKT PH-PIP3 interaction. Western blotting was used to determine the effects of the inhibitors on AKT activation in cancer cells, and in silico docking was used for structural analysis and optimization of inhibitor structure. Several flavonoids showing up to 50% inhibition of the AKT PH-PIP3 interaction decreased the level of AKT activation at the cellular level. In addition, the modified flavonoid showed increased inhibitory effects and the approach would be applied to develop anticancer drug candidates. In this study, we provide a rationale for targeting the lipid-binding domain of AKT, rather than the catalytic kinase domain, in anticancer drug development.

• Bulletin of the Korean Chemical Society
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• 제28권8호
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• pp.1335-1340
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• 2007

β-Ketoacyl acyl carrier protein synthase (KAS) III is a particularly attractive target in the type II fatty acid synthetic pathway, since it is central to the initiation of fatty acid synthesis. Enterococcus faecalis, a Grampositive bacterium, is one of the major causes of hospital acquired infections. The rise of multidrug-resistant of most bacteria requires the development of new antibiotics, such as inhibition of the KAS III. In order to block the fatty acid synthesis by inhibition of KAS III, at first, three dimensional structure of Enterococcus faecalis KAS III (efKAS III) was determined by comparative homology modeling using MODELLER based on x-ray structure of Staphylococcus aureus KAS III (saKAS III) which is a gram-positive bacteria and is 36.1% identical in amino acid sequences with efKAS III. Since His-Asn-Cys catalytic triad is conserved in efKAS III and saKAS III, substrate specificity of efKAS III and saKAS III and the size of primer binding pocket of these two proteins are expected to be similar. Ligand docking study of efKAS III with naringenin and apigenin showed that naringenin docked more strongly with efKAS III than apigenin, resulting in the intensive hydrogen bond network between naringenin and efKAS III. Also, only naringenin showed antibacterial activity against E. faecalis at 256 μg/mL. This study may give practical implications of flavonoids for antimicrobial effects against E. faecalis.

• Journal of Microbiology and Biotechnology
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• 제30권9호
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• pp.1436-1442
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• 2020

Amylosucrase (ASase, E.C. 2.4.1.4) is capable of efficient glucose transfer from sucrose, acting as the sole donor molecule, to various functional acceptor compounds, such as polyphenols and flavonoids. An ASase variant from Deinococcus geothermalis, in which the 226^th alanine is replaced with asparagine (DgAS-A226N), shows increased polymerization activity due to changes in the flexibility of the loop near the active site. In this study, we further investigated how the mutation modulates the enzymatic activity of DgAS using molecular dynamics and docking simulations to evaluate interactions between the enzyme and phenolic compounds. The computational analysis revealed that the A226N mutation could induce and stabilize structural changes near the substrate-binding site to increase glucose transfer efficiency to phenolic compounds. Kinetic parameters of DgAS-A226N and WT DgAS were determined with sucrose and 4-methylumbelliferone (MU) as donor and acceptor molecules, respectively. The k_cat/K_m value of DgAS-A226N with MU (6.352 mM^-1min^-1) was significantly higher than that of DgAS (5.296 mM^-1min^-1). The enzymatic activity was tested with a small phenolic compound, hydroquinone, and there was a 1.4-fold increase in α-arbutin production. From the results of the study, it was concluded that DgAS-A226N has improved acceptor specificity toward small phenolic compounds by way of stabilizing the active conformation of these compounds.

• Asian Pacific Journal of Cancer Prevention
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• 제17권1호
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• pp.51-55
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• 2016

Phytochemical investigation of Pistacia integerrima has highlighted isolation of two known compounds naringenin (1) and dihydrokaempferol (2). A crude extract and these isolated compounds were here evaluated for their effects on reversion of multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). The multidrug resistance P-glycoprotein is a target for chemotherapeutic drugs from cancer cells. In the present study rhodamine-123 exclusion screening test on human mdr1 gene transfected mouse gene transfected L5178 and L5178Y mouse T-cell lymphoma cells showed excellent MDR reversing effects in a dose dependent manner. In-silico molecular docking investigations demonstrated a common binding site for Rhodamine123, and compounds naringenin and dihydrokaempferol. Our results showed that the relative docking energies estimated by docking softwares were in satisfactory correlation with the experimental activities. Preliminary interaction profile of P-gp docked complexes were also analysed in order to understand the nature of binding modes of these compounds. Our computational investigation suggested that the compounds interactions with the hydrophobic pocket of P-gp are mainly related to the inhibitory activity. Moreover this study s a platform for the discovery of novel natural compounds from herbal origin, as inhibitor molecules against the P-glycoprotein for the treatment of cancer.

• Asian Pacific Journal of Cancer Prevention
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• 제15권23호
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• pp.10345-10350
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• 2015

Background: Punica granatum (family: Lythraceae) is mainly found in Iran, which is considered to be its primary centre of origin. Studies on pomegranate peel have revealed antioxidant, anti-inflammatory, anti-angiogenesis activities, with prevention of premature aging and reducing inflammation. In addition to this it is also useful in treating various diseases like diabetes, maintaining blood pressure and treatment of neoplasms such as prostate and breast cancer. Objectives: In this study we identified anti-cancer targets of active compounds like corilagin (tannins), quercetin (flavonoids) and pseudopelletierine (alkaloids) present in pomegranate peel by employing dual reverse screening and binding analysis. Materials and Methods: The potent targets of the pomegranate peel were annotated by the PharmMapper and ReverseScreen 3D, then compared with targets identified from different Bioassay databases (NPACT and HIT's). Docking was then further employed using AutoDock pyrx and validated through discovery studio for studying molecular interactions. Results: A number of potent anti-cancerous targets were attained from the PharmMapper server according to their fit score and from ReverseScreen 3D server according to decreasing 3D scores. Conclusion: The identified targets now need to be further validated through in vitro and in vivo studies.