Publications by authors named "Gibeom Nam"

8 Publications

  • Page 1 of 1

Effect of hyperspectral image-based initial conditions on improving short-term algal simulation of hydrodynamic and water quality models.

J Environ Manage 2021 Sep 12;294:112988. Epub 2021 Jun 12.

School of Civil and Environmental Engineering, Konkuk University, Seoul 05029, Republic of Korea. Electronic address:

Hydrodynamic and water quality modeling have provided valuable simulation results that have enhanced the understanding of the spatial and temporal distribution of algal blooms. Typical model simulations are performed with point-based observational data that are used to configure initial and boundary conditions, and for parameter calibration. However, the application of such conventional modeling approaches is limited due to cost, labor, and time constraints that preclude the retrieval of high-resolution spatial data. Thus, the present study applied fine-resolution algal data to configure the initial conditions of a hydrodynamic and water quality model and compared the accuracy of short-term algal simulations with the results simulated using conventional point-based initial conditions. The environmental fluid dynamics code (EFDC) model was calibrated to simulate Chlorophyll-a (Chl-a) concentrations. Hyperspectral images were used to generate Chl-a maps based on a two-band ratio algorithm for configuring the initial condition of the EFDC model. The model simulation with hyperspectral-based initial conditions returned relatively accurate results for Chl-a, compared to the simulation based on point-based initial conditions. The simulations exhibited percent bias values of 9.93 and 14.23, respectively. Therefore, the results of this study demonstrate how hyperspectral-based initial conditions could improve the reliability of short-term algal bloom simulations in a hydrodynamic model.
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http://dx.doi.org/10.1016/j.jenvman.2021.112988DOI Listing
September 2021

Discovery of a simplified deguelin analog as an HSP90 C-terminal inhibitor for HER2-positive breast cancer.

Bioorg Med Chem Lett 2021 Aug 24;45:128134. Epub 2021 May 24.

College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. Electronic address:

A series of O-substituted analogs of the C-ring-truncated scaffold of deguelin designed as heat shock protein 90 (HSP90) C-terminal inhibitors were investigated as novel antitumor agents against human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Among the synthesized compounds, compound 37 displayed significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast cancer cells with little cytotoxicity to normal cells. Mechanistic studies of compound 37 carried out by HSP90α C-terminal inhibitor screening, the induction of the heat shock response and downregulation of HSP90 client proteins indicated that the antitumor activity of 37 in breast cancer cells could be attributed to the destabilization and inactivation of HSP90 client proteins by the binding of 37 to the C-terminal domain of HSP90. A molecular docking study of compound 37 with a HSP90 homology model indicated that its S-isomer fit well in the ATP binding site of the C-terminal domain, forming key interactions.
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http://dx.doi.org/10.1016/j.bmcl.2021.128134DOI Listing
August 2021

Predicting Cyanobacterial Blooms Using Hyperspectral Images in a Regulated River.

Sensors (Basel) 2021 Jan 13;21(2). Epub 2021 Jan 13.

Water Quality Assessment Research Division, Water Environment Research Department, National Institute of Environmental Research, Incheon 22689, Korea.

Process-based modeling for predicting harmful cyanobacteria is affected by a variety of factors, including the initial conditions, boundary conditions (tributary inflows and atmosphere), and mechanisms related to cyanobacteria growth and death. While the initial conditions do not significantly affect long-term predictions, the initial cyanobacterial distribution in water is particularly important for short-term predictions. Point-based observation data have typically been used for cyanobacteria prediction of initial conditions. These initial conditions are determined through the linear interpolation of point-based observation data and may differ from the actual cyanobacteria distribution. This study presents an optimal method of applying hyperspectral images to establish the Environmental Fluid Dynamics Code-National Institute of Environment Research (EFDC-NIER) model initial conditions. Utilizing hyperspectral images to determine the EFDC-NIER model initial conditions involves four steps that are performed sequentially and automated in MATLAB. The EFDC-NIER model is established using three grid resolution cases for the Changnyeong-Haman weir section of the Nakdong River Basin, where dominates during the summer (July to September). The effects of grid resolution on (1) water quality modeling and (2) initial conditions determined using cumulative distribution functions are evaluated. Additionally, the differences in values are compared when applying initial conditions using hyperspectral images and point-based evaluation data. Hyperspectral images allow detailed initial conditions to be applied in the EFDC-NIER model based on the plane-unit cyanobacterial information observed in grids, which can reduce uncertainties in water quality (cyanobacteria) modeling.
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http://dx.doi.org/10.3390/s21020530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828484PMC
January 2021

A novel HSP90 inhibitor targeting the C-terminal domain attenuates trastuzumab resistance in HER2-positive breast cancer.

Mol Cancer 2020 11 20;19(1):161. Epub 2020 Nov 20.

Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 152-703, Republic of Korea.

Trastuzumab resistance in HER2-positive breast cancer is associated with a poorer prognosis. HSP90 is thought to play a major role in such resistance, but N-terminal inhibitors of this target have had little success. We sought to investigate the utility of NCT-547, a novel, rationally-designed C-terminal HSP90 inhibitor in the context of overcoming trastuzumab resistance. NCT-547 treatment significantly induced apoptosis without triggering the heat shock response (HSR), accompanied by caspase-3/- 7 activation in both trastuzumab-sensitive and -resistant cells. NCT-547 effectively promoted the degradation of full-length HER2 and truncated p95HER2, while also attenuating hetero-dimerization of HER2 family members. The impairment of cancer stem-like traits was observed with reductions in ALDH1 activity, the CD24/CD44 subpopulation, and mammosphere formation in vitro and in vivo. NCT-547 was an effective inhibitor of tumor growth and angiogenesis, and no toxic outcomes were found in initial hepatic and renal analysis. Our findings suggest that NCT-547 may have applications in addressing trastuzumab resistance in HER2-positive breast cancer.
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http://dx.doi.org/10.1186/s12943-020-01283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678296PMC
November 2020

Discovery of novel anti-breast cancer agents derived from deguelin as inhibitors of heat shock protein 90 (HSP90).

Bioorg Med Chem Lett 2020 09 2;30(17):127374. Epub 2020 Jul 2.

College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.

A series of O-substituted analogues of the B,C-ring truncated scaffold of deguelin were designed as C-terminal inhibitors of heat shock protein 90 (HSP90) and investigated as novel antiproliferative agents against HER2-positive breast cancer. Among the synthesized compounds, compound 80 exhibited significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast cancer cells, whereas compound 80 did not show any cytotoxicity in normal cells. Compound 80 markedly downregulated the expression of the major client proteins of HSP90 in both cell types, indicating that the cytotoxicity of 80 in breast cancer cells is attributed to the destabilization and inactivation of HSP90 client proteins and that HSP90 inhibition represents a promising strategy to overcome trastuzumab resistance. A molecular docking study of 80 with the homology model of a HSP90 homodimer showed that 80 fit nicely in the C-terminal domain with a higher electrostatic complementary score than that of ATP.
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http://dx.doi.org/10.1016/j.bmcl.2020.127374DOI Listing
September 2020

Antithrombotic effect of SP-8008, a benzoic acid derivative, through the selective inhibition of shear stress-induced platelet aggregation.

Br J Pharmacol 2020 02 21;177(4):929-944. Epub 2020 Jan 21.

College of Pharmacy, Seoul National University, Seoul, Korea.

Background And Purpose: Bleeding is one of the most critical adverse effects of antithrombotic drugs, and many efforts have been made to discover novel antiplatelet agents without bleeding complications. Shear stress-induced platelet aggregation (SIPA), where the interaction of von Willebrand factor (vWF) and platelet glycoprotein (GP) Ib constitutes the initial step, is a promising target to overcome bleeding problems, as SIPA occurs only in pathological conditions. Here, we describe SP-8008, a novel modulator of vWF-GP Ib interactions and evaluated its antiplatelet/antithrombotic effects.

Experimental Approach: Newly synthesized compounds were screened for antiplatelet effects in vitro, using human platelets exposed to high shear stress. Aggregation, intracellular calcium level, granule secretion, and integrin activation were assessed. Molecular modelling using virtual docking and flow cytometry were used to evaluate effects on vWF-GP Ib interactions. Antithrombotic effects in vivo were determined in rats, using arterial thrombosis and shear stress-specific thrombosis. Transection tail bleeding time was used to evaluate adverse effects.

Key Results: SP-8008 was a potent inhibitor of SIPA, with IC of 1.44 ± 0.09 μM. SP-8008 effectively and broadly blocked shear stress-induced platelet activation events, without any significant toxicity. Importantly, SP-8008 was highly selective against SIPA, effectively interfering with vWF-GP Ib engagement. Most importantly, SP-8008 exerted significant antithrombotic effects in vivo in both shear stress-specific and arterial thrombosis, without prolonging bleeding time.

Conclusions And Implications: Our results demonstrated that SP-8008 can be a novel selective antiplatelet agent with improved safety profile.
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http://dx.doi.org/10.1111/bph.14894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024737PMC
February 2020

Identification of a novel S6K1 inhibitor, rosmarinic acid methyl ester, for treating cisplatin-resistant cervical cancer.

BMC Cancer 2019 Aug 6;19(1):773. Epub 2019 Aug 6.

School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.

Background: The mTOR/S6K1 signaling pathway is often activated in cervical cancer, and thus considered a molecular target for cervical cancer therapies. Inhibiting mTOR is cytotoxic to cervical cancer cells and creates a synergistic anti-tumor effect with conventional chemotherapy agents. In this study, we identified a novel S6K1 inhibitor, rosmarinic acid methyl ester (RAME) for the use of therapeutic agent against cervical cancer.

Methods: Combined structure- and ligand-based virtual screening was employed to identify novel S6K1 inhibitors among the in house natural product library. In vitro kinase assay and immunoblot assay was used to examine the effects of RAME on S6K1 signaling pathway. Lipidation of LC3 and mRNA levels of ATG genes were observed to investigate RAME-mediated autophagy. PARP cleavage, mRNA levels of apoptotic genes, and cell survival was measured to examine RAME-mediated apoptosis.

Results: RAME was identified as a novel S6K1 inhibitor through the virtual screening. RAME, not rosmarinic acid, effectively reduced mTOR-mediated S6K1 activation and the kinase activity of S6K1 by blocking the interaction between S6K1 and mTOR. Treatment of cervical cancer cells with RAME promoted autophagy and apoptosis, decreasing cell survival rate. Furthermore, we observed that combination treatment with RAME and cisplatin greatly enhanced the anti-tumor effect in cisplatin-resistant cervical cancer cells, which was likely due to mTOR/S6K1 inhibition-mediated autophagy and apoptosis.

Conclusions: Our findings suggest that inhibition of S6K1 by RAME can induce autophagy and apoptosis in cervical cancer cells, and provide a potential option for cervical cancer treatment, particularly when combined with cisplatin.
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http://dx.doi.org/10.1186/s12885-019-5997-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683399PMC
August 2019

Structure-activity relationship study of thiazolyl-hydroxamate derivatives as selective histone deacetylase 6 inhibitors.

Bioorg Med Chem 2019 08 20;27(15):3408-3420. Epub 2019 Jun 20.

School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea. Electronic address:

Several human diseases are associated with aberrant epigenetic pathways mediated by histone deacetylases (HDACs), especially HDAC6, a class IIb HDACs, which has emerged as an attractive target for neurodegenerative and autoimmune disease therapeutics. In a previous study, we developed the novel HDAC6-selective inhibitor 9a ((E)-N-hydroxy-4-(2-styrylthiazol-4-yl)butanamide) and showed that it has anti-sepsis activity in vivo. In this study, we conducted structure-activity relationship (SAR) studies to optimize the activity and selectivity of HDAC6, synthesizing its derivatives with various aliphatic linker sizes and cap structures. We identified 6u ((E)-N-hydroxy-3-(2-(4-fluorostyryl)thiazol-4-yl)propanamide), which has nanomolar inhibition activity and a 126-fold selectivity for HDAC6 over HDAC1. Through the docking analyses of 6u against HDAC subtypes, we revealed the importance of the optimal aliphatic linker size, as well as the electronic substituent effect and rigidity of the aryl cap group. Thus, we suggest a new rationale for the design of HDAC6-selective inhibitors.
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http://dx.doi.org/10.1016/j.bmc.2019.06.036DOI Listing
August 2019
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