https://scholar.gist.ac.kr/handle/local/7973 2026-08-14T03:21:43Z https://scholar.gist.ac.kr/handle/local/32672 Title: Upregulation of arginase-II in osteoarthritic chondrocytes: Author(s): Wihak Kim Abstract: Osteoarthritis (OA) is characterized by cartilage destruction and occurs to be related to various metabolic disorders. However, in OA pathogenesis, mechanism of pathological effect of amino acids has not been clearly identified to date. We herein demonstrate that alterations of amino acid metabolism are important to OA pathogenesis in mice. Our microarray analysis showed that arginase-II (Arg-II) expression was significantly increased in mouse chondrocytes under various osteoarthritic conditions. Arg-II was also upregulated in mouse OA chondrocytes induced by various catabolic regulators and in OA cartilage of human and various mouse models. Moreover, Arg-II overexpressed by using Adenoviral systems in mouse chondrocytes and knee joint tissues lead to OA pathogenesis. Our findings demonstrate that Arg-II is a novel catabolic regulator of OA pathogenesis and could be a potential therapeutic target for the treatment of OA. 2018-12-31T15:00:00Z https://scholar.gist.ac.kr/handle/local/19875 Title: Unravelling the anti-cancer mechanism of small molecule drugs that modulate novel target in the tumor microenvironment Author(s): Taejoon Yoon Abstract: The tumor microenvironment (TME) is composed of intratumoral cell groups such as vascular cells, stromal cells or immune cells and even extracellular substrates or hypoxia. Of the many components that compose the TME, cancer-associated fibroblasts (CAF) and tumor-associated macrophage (TAM) are key components. CAF are activated compared to normal, tissue resident fibroblasts. CAF express marker genes and secrete specific cytokines at a greater rate than normal fibroblasts. Moreover, TAM show a phenotype that reflects their tumor origin and is distinct from normal macrophages or related-immune cells. There is an intercellular communication (termed crosstalk) between CAF and TAM than regulate tumor growth and metastasis. Previous research has shown that the cytokines IL-6 or GM-CSF are a key component of the crosstalk between CAF and TAM. In this thesis, FDA approved drugs were screened to select candidates that can target the IL-6 and downstream JAK/STAT signaling pathway in CAF. The MTT assay and ELISA were used to test CAF viability IL-6 cytokine expression, respectively. A hit drug, termed NDT-SOR, was selected as a best candidate. NDT-SOR downregulated IL-6 expression in human CAFs and immortalized hTERT fibroblasts stimulated by cancer cell YD-10B conditioned media (CM). Using western blotting, it was shown that NDT-SOR downregulates the expression of some members of the JAK/STAT pathway. Using co-culture assays with CAF, NDT-SOR was found to restrict monocyte differentiation and polarization into macrophages. Furthermore, these NDT-SOR treated monocytes showed reduced expression of TAM-specific genes, such as IL-10 or CD-206, compared to normal monocytes after co-culture. Additionally, invasion assay analyses show that NDT-SOR treatment reduced the ability of TAM to induce cancer cell migration. These results indicate that there are some crosstalk between CAF, TAM and cancer cells, and also NDT-SOR was newly discovered to be a drug that could inhibit the crosstalk, confirming the possibility of being a potential drug. 2022-12-31T15:00:00Z https://scholar.gist.ac.kr/handle/local/19844 Title: Toll-like receptor 5 from Ctenopharyngodon idella Author(s): Ham Suah Abstract: TLR5 is a pattern recognition receptor involved in the innate immune response. It is highly expressed on the cell membranes of intestine epithelial cells and dendritic cells, and it is the only human TLR known to bind a protein ligand. The ligand for TLR5 is bacterial flagellin, which binds to TLR5, inducing dimerization and triggering the innate immune response. Consequently, defects in TLR5 can impact inflammatory diseases of the gut, autoimmune diseases, and cancer cell growth. While the structure of zebrafish TLR5-LRR14 VLR in complex with flagellin has been determined through X-ray crystallography, understanding the precise mechanisms of flagellin recognition and signal transduction by TLR5 requires the full-length structure. In this study, I expressed Ctenopharyngodon idella (Grass carp) Toll-like receptor 5a and 5b, and using Cryo-EM, I determined the structures of TLR5a in its apo state, both as a dimer and a tetramer. 2023-12-31T15:00:00Z https://scholar.gist.ac.kr/handle/local/33847 Title: Therapeutic target discovery and drug development for sarcopenia and cancer Author(s): Kyounghwan Joo Abstract: Skeletal muscles constitute approximately 35% of total body weight and plays essential roles in support, movement, and metabolism. Muscle regeneration, primarily driven by muscle satellite cells (MuSCs), is crucial for maintaining muscle homeostasis. However, the myogenic capacity of MuSCs declines with age, leading to age related muscle atrophy known as sarcopenia. Therefore, identifying therapeutic targets that regulate skeletal muscle regeneration has significant potential for treating sarcopenia. In this study, we identify carbonic anhydrase 3 (Car3) as a novel regulator of skeletal muscle regeneration and myogenesis. Inhibition of Car3 enhances skeletal muscle regeneration and restores the regenerative capacity of aged satellite cells by activating non-canonical AKT-GSK3β-PGC1α signaling to promote mitochondrial function and myogenesis. These findings suggest Car3 as a potential therapeutic target for sarcopenia. This study provides the first evidence showing that Car3, previously considered a negative target for muscle atrophy, is therapeutically relevant as a promoter of skeletal muscle regeneration. Additionally, sarcopenia can occur due to an imbalance between protein degradation and synthesis, where muscle protein breakdown exceeds protein synthesis. This process arises from the excessive activation of factors involved in protein degradation, such as the ubiquitin-proteasome system (UPS). Specifically, the UPS is regulated by the transcriptional activity of the transcription factor FoxO3. In aged muscle, excessive transcriptional activity of FoxO3 leads to the overexpression of E3 ligase genes such as Atrogin-1 and MuRF-1, which in turn contributes to sarcopenia. FoxO3 also functions as a transcription factor regulating the expression of cell death-related genes in cancer cells. Activation of FoxO3 in cancer cells induces cell death by expressing cell death genes such as FasL and Bim. Therefore, in this study, we introduced a screening system capable of measuring FoxO3's transcriptional activity to select FoxO3 activators as anticancer therapeutic candidates and FoxO3 suppressors as sarcopenia therapeutic candidates. We screened a total of 2,484 compounds: 1,016 from an FDA-approved library and 1,468 from a natural compound library. Compound A was identified as a FoxO3 transcriptional activity inhibitor, and compound B was identified as a FoxO3 transcriptional activity activator. Compound A restored 51.04% of the atrophy in C2C12 myotubes induced by Dexamethasone, while compound B reduced the survival rate of HCT116 cells by 60.02% without affecting the survival rate of normal CCD18-CO cells. Overall, we identified Car3 as a novel factor regulating muscle regeneration. And by screening FoxO3 transcription activators and inhibitors, we discovered candidate compounds for sarcopenia treatment and anticancer therapy, thereby presenting new possibilities for promoting muscle regeneration, treating sarcopenia, and advancing anticancer treatment. 2025-12-31T15:00:00Z