• Applied Chemistry for Engineering
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• v.21 no.6
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• pp.593-602
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• 2010

Chitosan as a natural polymer has superior physicochemical properties such as biocompatibility, biodegradability and nontoxicity, but application of chitosan for therapy of cancer and gene related-disease has been limited by poor solubility in aqueous solution. Therefore, low molecular weight water-soluble chitosan (LMWSC) with high reactivity and strong positive charge can be applied as a delivery system having function to carry in the specific tissue the bioactive material like poor solubility drug, or therapeutic gene and developed as a therapeutic system having good therapeutic efficiency. The most important factor for therapy of various diseases is to reveal the antigen or receptor expressed in specific lesion tissue and the antibody and ligand which can bind with antigen is to introduce at the biomaterials for enhancement the therapeutic efficiency. The studies for cationic synthetic polymer as drug or gene delivery have been actively performed, but it has many problems such as toxicity in the body, therapeutic efficiency. From this point of view, this article demonstrated the introduction of functional groups to target the specific tissue and therapeutic strategy using the modification of LMWSC with free-amine group. The development of these delivery system will provide a positive vision for cancer therapy.

• Bulletin of the Korean Chemical Society
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• v.35 no.9
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• pp.2655-2659
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• 2014

Dual specificity protein phosphatase 4 (DUSP4) has been considered a promising target for the development of therapeutics for various human cancers. Here, we report the first example for a successful application of the structure-based virtual screening to identify the novel small-molecule DUSP4 inhibitors. As a consequence of the virtual screening with the modified scoring function to include an effective molecular solvation free energy term, five micromolar DUSP4 inhibitors are found with the associated $IC_{50}$ values ranging from 3.5 to $10.8{\mu}M$. Because these newly identified inhibitors were also screened for having desirable physicochemical properties as a drug candidate, they may serve as a starting point of the structure-activity relationship study to optimize the medical efficacy. Structural features relevant to the stabilization of the new inhibitors in the active site of DUSP4 are discussed in detail.

• BMB Reports
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• v.48 no.1
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• pp.30-35
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• 2015

This study was to investigate the role of Fas in the development of Cisplatin-resistant ovarian cancer. On the cellular level, Fas expression was significantly reduced in Cisplatin resistant A2780 (A2780/CP) cells compared with A2780 cells. Fas silence with siRNA would promote tumor cell lines proliferation, facilitate tumor cell cycle transition of G1/S, prevent cell apoptosis, and promote cell migration. Expression of drug resistance gene was negatively correlated to Fas. In nude mice metastasis model of human ovarian carcinoma by subcutaneous transplantation, after Ad-Fas injected intratumorly, we found that upregulation of Fas could inhibit transplantation tumor tissue growth and reduce the expression of drug resistance gene. Our results indicated that upregulation of Fas in epithelial ovarian cancer reversed the development of resistance to Cisplatin. In conclusion, our findings suggested that Fas might act as a promising therapeutic target for improvement of the sensibility to Cisplatin in ovarian cancer.

• Microbiology and Biotechnology Letters
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• v.25 no.4
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• pp.391-395
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• 1997

It was proved that both ethanol extracts from Mori Folium from Kangwon do and silk worm had higher inhibition acitivity on $\alpha$-glucohydrolase than the water extracts. In adding above 8.5 (mg/L) of silkworm extracts, the inhibition rate on $\alpha$-1,4 glucosidase was saturated while the inhibition rate was continuously increased in adding the extracts from Moli Folium. It was also found that the diethyl ether fraction showed much better inhibition activity than water fraction from ethanol extracts, yielding ca. 85% of inhibition rate for the extract of Moli Folium, compared to 91% for a commercially available hypoglycemic drug, Chloropropamide. In separating the diethyl ether fractions by Consecutive Sephadex gel filtration and Thin layer chromatography, three and four active spots were obtained from Moli Folium and silkworm, respectively. It is interesting that the similar Rf spots from both species among several spots in TLC have the highest inhibition acitivity on a target enzyme, which can imply that the active substances from both species are same or similar molecular weight and structure. Glucose-lowering activities of both speciese were also examined in vivo, showing that the fraction from Moli Folium had better activity than that from silkworm, and its activity was similar to that of a commercial drug.

• BMB Reports
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• v.51 no.5
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• pp.219-224
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• 2018

Necroptosis is an emerging form of programmed cell death occurring via active and well-regulated necrosis, distinct from apoptosis morphologically, and biochemically. Necroptosis is mainly unmasked when apoptosis is compromised in response to tumor necrosis factor alpha. Unlike apoptotic cells, which are cleared by macrophages or neighboring cells, necrotic cells release danger signals, triggering inflammation, and exacerbating tissue damage. Evidence increasingly suggests that programmed necrosis is not only associated with pathophysiology of disease, but also induces innate immune response to viral infection. Therefore, necroptotic cell death plays both physiological and pathological roles. Physiologically, necroptosis induce an innate immune response as well as premature assembly of viral particles in cells infected with virus that abrogates host apoptotic machinery. On the other hand, necroptosis per se is detrimental, causing various diseases such as sepsis, neurodegenerative diseases and ischemic reperfusion injury. This review discusses the signaling pathways leading to necroptosis, associated necroptotic proteins with target-specific inhibitors and diseases involved. Several studies currently focus on protective approaches to inhibiting necroptotic cell death. In cancer biology, however, anticancer drug resistance severely hampers the efficacy of chemotherapy based on apoptosis. Pharmacological switch of cell death finds therapeutic application in drug- resistant cancers. Therefore, the possible clinical role of necroptosis in cancer control will be discussed in brief.

• The Korean Journal of Physiology and Pharmacology
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• v.20 no.6
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• pp.573-580
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• 2016

Caspases, a family of cysteine proteases, cleave substrates and play significant roles in apoptosis, autophagy, and development. Recently, our group identified 72 genes that interact with Death Caspase-1 (DCP-1) proteins in Drosophila by genetic screening of 15,000 EP lines. However, the cellular functions and molecular mechanisms of the screened genes, such as their involvement in apoptosis and autophagy, are poorly understood in mammalian cells. In order to study the functional characterizations of the genes in human cells, we investigated 16 full-length human genes in mammalian expression vectors and tested their effects on apoptosis and autophagy in human cell lines. Our studies revealed that ALFY, BIRC4, and TAK1 induced autophagy, while SEC61A2, N-PAC, BIRC4, WIPI1, and FALZ increased apoptotic cell death. BIRC4 was involved in both autophagy and apoptosis. Western blot analysis and luciferase reporter activity indicated that ALFY, BIRC4, PDGFA, and TAK1 act in a p53-dependent manner, whereas CPSF1, SEC61A2, N-PAC, and WIPI1 appear to be p53-independent. Overexpression of BIRC4 and TAK1 caused upregulation of p53 and accumulation of its target proteins as well as an increase in p53 mRNA levels, suggesting that these genes are involved in p53 transcription and expression of its target genes followed by p53 protein accumulation. In conclusion, apoptosis and/or autophagy mediated by BIRC4 and TAK1 may be regulated by p53 and caspase activity. These novel findings may provide valuable information that will aid in a better understanding of the roles of caspase-related genes in human cell lines and be useful for the process of drug discovery.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.3
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• pp.1105-1109
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• 2015

Chemoresistance is the most common cause of chemotherapy failure during breast cancer (BCA) treatment. It is generally known that the mechanisms of chemoresistance in tumors involve multiple genes and multiple signaling pathways,; if appropriate drugs are used to regulate the mechanisms at the gene level, it should be possible to effectively reverse chemoresistance in BCA cells. It has been confirmed that chemoresistance in BCA cells could be reversed by ginsenoside Rh2 (G-Rh2). Preliminary studies of our group identified some drugresistance specific miRNA. Accordingly, we proposed that G-Rh2 could mediate drug-resistance specific miRNA and corresponding target genes through the gene regulatory network; this could cut off the drug-resistance process in tumors and enhance treatment effects. G-Rh2 and breast cancer cells were used in our study. Through pharmaceutical interventions, we could explore how G-Rh2 could inhibit chemotherapy resistance in BCA, and analyze its impact on related miRNA and target genes. Finally, we will reveal the anti-resistance molecular mechanisms of G-Rh2 from a different angle in miRNA-mediated chemoresistance signals among cells.

• Journal of TMJ Balancing Medicine
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• v.10 no.1
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• pp.12-20
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• 2020

Objectives: Tourette syndrome (TS) is a disease that occurs evenly in many social classes. Despite the long experience of drug treatment, the preference is low due to various side effects. The aim of this study was to discover herbal medicine resources through network pharmacology analysis predicted to be useful for Tourette syndrome. Methods: We used Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) to identify herbal medicines that can be used for TS by using network pharmacology research methods and to predict the mechanism of action. After evaluating compounds of each identified herb, molecular target proteins and mechanisms of action were analyzed, focusing on compounds that are likely to exhibit clinical activity in consideration of the pharmacokinetic parameters of these individual compounds. Results: Fifty nine ingredients such as atropine, veraguensin, and nuciferin among the compounds contained in 48 types of medicinal herbs such as Daturae Flos (洋金花), Salviae Radix (丹参), and Nelumbinis Plumula (蓮子心) act on the D(2) dopamine receptor, which is a protein involved in the development of TS. It has been found that atropine, veraguensin, and nuciferin are highly likely to exhibit activity by acting on the G protein-coupled receptor signaling pathway. Conclusions: It can be used in conjunction with non-invasive treatment means such as FCST Yinyang Balancing Appliance with herbal therapy to bring about a significant therapeutic effect, and it will be possible to develop a treatment that can replace drug therapy used in Western medicine.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.12
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• pp.7473-7482
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• 2013

The G-protein coupled receptor 87 (GPR87) is a recently discovered orphan GPCR which means that the search of their endogenous ligands has been a novel challenge. GPR87 has been shown to be overexpressed in squamous cell carcinomas (SCCs) or adenocarcinomas in lungs and bladder. The 3D structure of GPR87 was here modeled using two templates (2VT4 and 2ZIY) by a threading method. Functional assignment of GPR87 by SVM revealed that along with transporter activity, various novel functions were predicted. The 3D structure was further validated by comparison with structural features of the templates through Verify-3D, ProSA and ERRAT for determining correct stereochemical parameters. The resulting model was evaluated by Ramachandran plot and good 3D structure compatibility was evidenced by DOPE score. Molecular dynamics simulation and solvation of protein were studied through explicit spherical boundaries with a harmonic restraint membrane water system. A DRY-motif (Asp-Arg-Tyr sequence) was found at the end of transmembrane helix3, where GPCR binds and thus activation of signals is transduced. In a search for better inhibitors of GPR87, in silico modification of some substrate ligands was carried out to form polar interactions with Arg115 and Lys296. Thus, this study provides early insights into the structure of a major drug target for SCCs.

• Bulletin of the Korean Chemical Society
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• v.35 no.8
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• pp.2494-2504
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• 2014

P38 mitogen activated protein (MAP) kinase is an important anti-inflammatory drug target, which can be activated by responding to various stimuli such as stress and immune response. Based on the conformation of the conserved DFG loop (in or out), binding inhibitors are termed as type-I and II. Type-I inhibitors are ATP competitive, whereas type-II inhibitors bind in DFG-out conformation of allosteric pocket. It remains unclear that how these allosteric inhibitors stabilize the DFG-out conformation and interact. Organosilicon compounds provide unusual opportunity to enhance potency and diversity of drug molecules due to their low toxicity. However, very few examples have been reported to utilize this property. In this regard, we performed docking of an inhibitor (BIRB) and its silicon analog (Si-BIRB) in an allosteric binding pocket of p38. Further, molecular dynamics (MD) simulations were performed to study the dynamic behavior of the simulated complexes. The difference in the biological activity and mechanism of action of the simulated inhibitors could be explained based on the molecular mechanics/generalized Born surface area (MM/GBSA) binding free energy per residue decomposition. MM/GBSA showed that biological activities were related with calculated binding free energy of inhibitors. Analyses of the per-residue decomposed energy indicated that van der Waals and non-polar interactions were predominant in the ligand-protein interactions. Further, crucial residues identified for hydrogen bond, salt bridge and hydrophobic interactions were Tyr35, Lys53, Glu71, Leu74, Leu75, Ile84, Met109, Leu167, Asp168 and Phe169. Our results indicate that stronger hydrophobic interaction of Si-BIRB with the binding site residues could be responsible for its greater binding affinity compared with BIRB.