• Journal of Microbiology
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• v.42 no.4
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• pp.361-364
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• 2004

Internal ribosome entry site (IRES) of the hepatitis C virus (HCV) is known to be essential for HCV replication and most conserved among HCV variants. Hence, IRES RNA is a good therapeutic target for RNA-based inhibitors, such as ribozymes. We previously proposed a new anti-HCV modulation strategy based on trans-splicing ribozymes, which can selectively replace HCV transcripts with a new RNA that exerts anti-HCV activity. To explore this procedure, sites which are accessible to ribozymes in HCV IRES were previously determined by employing an RNA mapping method in vitro. In this study, we evaluate the intracellular accessibility of the ribozymes by comparing the trans-splicing activ­ities in cells of several ribozymes targeting different sites of the HCV IRES RNA. We assessed the intra­cellular activities of the ribozymes by monitoring their target-specific induction degree of both reporter gene activity and cytotoxin expression. The ribozyme capable of targeting the most accessible site iden­tified by the mapping studies then harbored the most active trans-splicing activity in cells. These results suggest that the target sites predicted to be accessible are truly the most accessible in the cells, and thus, could be applied to the development of various RNA-based anti-HCV therapies.

• Biomolecules & Therapeutics
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• v.23 no.6
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• pp.493-509
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• 2015

Antibody-drug conjugates utilize the antibody as a delivery vehicle for highly potent cytotoxic molecules with specificity for tumor-associated antigens for cancer therapy. Critical parameters that govern successful antibody-drug conjugate development for clinical use include the selection of the tumor target antigen, the antibody against the target, the cytotoxic molecule, the linker bridging the cytotoxic molecule and the antibody, and the conjugation chemistry used for the attachment of the cytotoxic molecule to the antibody. Advancements in these core antibody-drug conjugate technology are reflected by recent approval of Adectris$^{(R)}$(anti-CD30-drug conjugate) and Kadcyla$^{(R)}$(anti-HER2 drug conjugate). The potential approval of an anti-CD22 conjugate and promising new clinical data for anti-CD19 and anti-CD33 conjugates are additional advancements. Enrichment of antibody-drug conjugates with newly developed potent cytotoxic molecules and linkers are also in the pipeline for various tumor targets. However, the complexity of antibody-drug conjugate components, conjugation methods, and off-target toxicities still pose challenges for the strategic design of antibody-drug conjugates to achieve their fullest therapeutic potential. This review will discuss the emergence of clinical antibody-drug conjugates, current trends in optimization strategies, and recent study results for antibody-drug conjugates that have incorporated the latest optimization strategies. Future challenges and perspectives toward making antibody-drug conjugates more amendable for broader disease indications are also discussed.

• Journal of the Korean Society of Physical Medicine
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• v.13 no.3
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• pp.141-150
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• 2018

PURPOSE: This study was conducted to understand the adaptive responses of different modes of physical exercises utilizing skeletal muscle and the comprehensive relevance of AMPK signaling that can be activated by physical exercise as a potential molecular target in human health problems such as neuromuscular disorders (NMDs). METHODS: Most of the contents in this review article are based on recent publications concerning the main topics of interest. The reference literatures cited were obtained by basic searches of overseas academic databases such as PubMed and ScienceDirect using EndNote X7.8. RESULTS: The phenotypic adaptive responses of skeletal muscle during endurance- and resistance-based exercise training (ET and RT respectively) appear to be distinct. To explain the adaptive responses in each single mode of exercises (ET, RT) along with combined exercise training (CT), AMPK signaling is proposed as an important molecular link among those differential modes of exercise and a promising molecular target of NMDs. CONCLUSION: Based on the available evidence, intracellular AMPK signaling activated by diverse stimuli including physical exercise can be a potential and promising therapeutic target for the prevention, amelioration or cure of various human health problems including NMDs and may also be beneficial for physical rehabilitation and emergency situations that may elicit acute metabolic stresses.

• The Korean Journal of Physiology and Pharmacology
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• v.17 no.5
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• pp.375-383
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• 2013

Hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV) and hepatitis C virus (HCV) infections is thought to account for more than 80% of primary liver cancers. Both HBV and HCV can establish chronic liver inflammatory infections, altering hepatocyte and liver physiology with potential liver disease progression and HCC development. Cyclophilin A (CypA) has been identified as an essential host factor for the HCV replication by physically interacting with the HCV non structural protein NS5A that in turn interacts with RNA-dependent RNA polymerase NS5B. CypA, a cytosolic binding protein of the immunosuppressive drug cyclosporine A, is overexpressed in many cancer types and often associated with malignant transformation. Therefore, CypA can be a good target for molecular cancer therapy. Because of antiviral activity, the CypA inhibitors have been tested for the treatment of chronic hepatitis C. Nonimmunosuppressive Cyp inhibitors such as NIM811, SCY-635, and Alisporivir have attracted more interests for appropriating CypA for antiviral chemotherapeutic target on HCV infection. This review describes CypA inhibitors as a potential HCC treatment tool that is contrived by their obstructing chronic HCV infection and summarizes roles of CypA in cancer development.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.3681-3685
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• 2012

Background: In breast cancer, estrogen receptors have been demonstrated to interact with transcription factors to regulate target gene expression. However, high-throughput identification of the transcription regulation relationship between transcription factors and their target genes in response to estradiol is still in its infancy. Purpose: Thus, the objective of our study was to interpret the transcription regulation network of MCF7 breast cancer cells exposed to estradiol. Methods: In this work, GSE11352 microarray data were used to identify differentially expressed genes (DEGs). Results: Our results showed that the MYB (v-myb myeloblastosis viral oncogene homolog [avian]), PGR (progesterone receptor), and MYC (v-myc myelocytomatosis viral oncogene homolog [avian]) were hub nodes in our transcriptome network, which may interact with ER and, in turn, regulate target gene expression. MYB can up-regulate MCM3 (minichromosome maintenance 3) and MCM7 expression; PGR can suppress BCL2 (B-cell lymphoma 2) expression; MYC can inhibit TGFB2 (transforming growth factor, beta 2) expression. These genes are associated with breast cancer progression via cell cycling and the $TGF{\beta}$ signaling pathway. Conclusion: Analysis of transcriptional regulation may provide a better understanding of molecular mechanisms and clues to potential therapeutic targets in the treatment of breast cancer.

• Nuclear Engineering and Technology
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• v.40 no.7
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• pp.551-560
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• 2008

Radiation has stochastic aspects in its generation, its choice of interaction mode during traveling in media, and its impact on living bodies. In certain circumstances, like in high dose environments resulting from low-LET radiation, the variance in its impact on a target volume is negligible. On the contrary, in low dose environments, especially when they are attributed to high-LET radiation, the impact on the target carries with it a large variance. This variation is more significant for smaller target volumes. Microdosimetric techniques, which have been developed to estimate the distribution of radiation energy deposited to cellular and subcellular-sized targets, contrast with macrodosimetric techniques which count only the average value. Since cells and DNA compounds are the critical targets in human bodies, microdosimetry, or dose estimation by microscopic approach, helps one better analyze the biological effects of radiation on the human body. By utilizing microbeam systems designed for individual cell irradiation, scientists have discovered that human cells exhibit radiosensitive reactions without being hit themselves (bystander effect). During the past 10 or more years, a new therapeutic protocol using discontinuous multiple micro-slit beams has been investigated for its clinical application. It has been suggested that the beneficial bystander effect is the essence of this protocol.

• BMB Reports
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• v.42 no.8
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• pp.535-539
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• 2009

Voltage-gated $K^+$ (Kv) channels are widely expressed in the plasma membranes of numerous cells such as epithelial cells. Recently, it has been demonstrated that Kv channels are associated with the proliferation of several types of cancer cells. Specifically, Kv1.3 seems to be involved in cancer cell proliferation and apoptosis. In the present study, we examined the expression of Kv1.3 in immortalized and tumorigenic human mammary epithelial cells. We also evaluated the expression level of Kv1.3 in each stage of breast cancer using mRNA isolated from breast cancer patients. In addition, treatment with tetraethylammonium, a Kv channel blocker, suppressed tumorigenic human mammary epithelial cell proliferation. Therefore, Kv1.3 may serve as a novel molecular target for breast cancer therapy while its stage-specific expression pattern may provide a potential diagnostic marker for breast cancer development.

• Genomics & Informatics
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• v.21 no.1
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• pp.5.1-5.13
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• 2023

Neisseria gonorrhoeae is a Gram-negative aerobic diplococcus bacterium that primarily causes sexually transmitted infections through direct human sexual contact. It is a major public health threat due to its impact on reproductive health, the widespread presence of antimicrobial resistance, and the lack of a vaccine. In this study, we used a bioinformatics approach and performed subtractive genomic methods to identify potential drug targets against the core proteome of N. gonorrhoeae (12 strains). In total, 12,300 protein sequences were retrieved, and paralogous proteins were removed using CD-HIT. The remaining sequences were analyzed for non-homology against the human proteome and gut microbiota, and screened for broad-spectrum analysis, druggability, and anti-target analysis. The proteins were also characterized for unique interactions between the host and pathogen through metabolic pathway analysis. Based on the subtractive genomic approach and subcellular localization, we identified one cytoplasmic protein, 2Fe-2S iron-sulfur cluster binding domain-containing protein (NGFG RS03485), as a potential drug target. This protein could be further exploited for drug development to create new medications and therapeutic agents for the treatment of N. gonorrhoeae infections.

• Journal of Sasang Constitutional Medicine
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• v.35 no.4
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• pp.10-22
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• 2023

Objectives The aim of this study is to explore the mechanism of action and target diseases of Sasang constitutional prescriptions using a multiscale interactome approach. Methods The compound and target information of Sasang constitutional prescriptions were retrieved from various databases such as the TM-MC, STITCH, and TTD. Key targets for Sasang constitutional prescriptions were identified by selecting the top 100 targets based on the number of simple paths within the constructed network. Diffusion profiles for Sasang constitutional prescriptions and diseases were calculated based on a biased random walk algorithm. Potential diseases and key mechanisms of Sasang constitutional prescriptions were identified by analyzing diffusion profiles. Results We identified 144 Sasang constitutional prescriptions and their targets, finding 80 herbs with effective biological targets. A cluster analysis based on selecting up to 100 key targets for each prescription revealed a more cohesive grouping of prescriptions according to Sasang constitution. We then predicted potential diseases for 62 Sasang constitutional prescriptions using diffusion profiles calculated on a multiscale interactome. Finally, our analysis of diffusion profiles revealed key targets and biological functions of prescriptions in obesity and diabetes. Conclusions This study demonstrates the effectiveness of a multiscale interactome approach in elucidating the complex mechanisms and potential therapeutic applications of prescriptions in Sasang constitutional medicine.

• Oncology Letters
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• v.17 no.3
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• pp.2576-2582
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• 2019

Gestational trophoblastic disease (GTD) is an unusual disease occurring in pregnancy that originates from abnormal trophoblastic cells and comprises a group of diseases with different properties of invasion, metastasis and recurrence. The GTD group includes hydatidiform moles and gestational trophoblastic neoplasms (GTNs), with GTNs being divided into invasive moles, choriocarcinoma, placental site trophoblastic tumors and epithelioid trophoblastic tumors. The present review focuses on current effective treatments for GTD, including conventional and novel promising direct enzyme prodrug therapies (DEPTs). Conventional therapies, such as chemotherapy and hysterectomy, are currently used in a clinical setting; however, the use of diverse DEPTs, including antibody-DEPT and gene-DEPT is also being attempted to cure GTNs. In addition, gene delivery tools using genetically engineered neural stem cells (NSCs) are presently being examined for the treatment of GTNs. The tumor-tropism of NSCs by chemoattractant factors is a unique characteristic of these cells and can serve as a vehicle to deliver anticancer agents. Previous studies have demonstrated that injection with NSC-expressing suicide genes into xenograft animal models has a significant inhibitory effect on tumor growth. Stem cells can be genetically engineered to express anticancer genes, which migrate to the metastatic sites and selectively target cancer cells, and are considered to effectively target metastatic GTNs. However, the safety issue of stem cell therapy, such as tumorigenesis, remains a challenge. Novel therapies comprising a combination of conventional and novel promising treatments are anticipated to be definitive treatments for metastasized and/or recurrent patients with GTNs.