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( Da-gyum Lee ),( Sungweon Ryoo ),( Yoohyun Hwang ),( Eun-jin Park ),( Jung-hyun Kim ) 대한결핵 및 호흡기학회 2021 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.129 No.-
Background Mycobacterium abscessus (M. abscessus) causes chronic pulmonary infections and is the most difficult Nontuberculous Mycobacteria (NTM) to treat due to its resistance to current antimicrobial drugs, with a treatment success rate of 45.6 %. Thus, novel treatment drugs are needed, of which we identified the drug Clomiphene Citrate (CC), which treats infertility in women, to exhibit inhibitory activity against M. abscessus. Methods To assess the potential of CC as a treatment for M. abscessus pulmonary diseases, we measured its efficacy in vitro and established the intracellular activity of CC against M. abscessus in human macrophages. Results CC significantly inhibited the growth of not only wild-type M. abscessus strains, but also clinical isolate strains and clarithromycin (CLR)-resistant strains of M. abscessus. CC’s drug-efficacy did not have a significant cytotoxicity in the infected macrophages. Furthermore, CC worked in anaerobic non-replicating conditions as well as in the presence of biofilm. Conclusions The Results of this in vitro study on M. abscessus activity suggest that CC is a potential new drug for the treatment of M. abscessus infections.
Intra-cellular activity of LCB01-0371, a novel oxazolidinone, against mycobacterium tuberculosis
( Da-gyum Lee ),( Tae Yoon Kim ),( Ji Hee Jung ),( Ji Yeon Kim ),( Sang Hee Park ),( Yun Ho Jung ),( Sung Weon Ryoo ) 대한결핵 및 호흡기학회 2019 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.127 No.-
Background: LCB01-0371 is a novel oxazolidinone compound containing a cyclic amidrazone group that shows potent anti-mycobacterial activities against most mycobacterial bacilli, including the multi-drug resistant tuberculosis. LCB01-0371 was evaluated for safety, tolerability, and pharmacokinetics in a recently completed phase I clinical trial. In this study, intracellular activity of LCB01-0371, against Mycobacterium tuberculosis was evaluated in comparison with that of Linezolid using macrophage infection models. Methods: Resazurin reduction microplate assay (REMA), was performed to determine the MIC of Mycobaterium tuberculosis against LCB01-0371 and linezolid. Human THP-1 macrophages were infected with H37Rv-GFP (MOI ratio 10). LCB01-0371 and linezolid treated each concentration for 5 days. Live cell microscopy using a automated live cell imager (BioTek Instruments). Fluorescent images of live cells were captured every 6 hrs for 5 days. Results: LCB01-0371 and linezolid exhibited minimum inhibitory concentration (MIC) values against Mycobacterium tuberculosis (H37Rv) 3.34uM and 0.55uM respectively. In a macrophage infection model, LCB01-0371 dramatically decreased the number of intracellular Mycobacterium tuberculosis bacilli at 5 days after infection at concentration range from 50 nM to 3.2 uM. LCB01 0371 and linezolid inhibited mycobacterial growth 28.54% and 21.76% respectively at concentration of 3.2 uM. Conclusions: Critically, we describe a class of oxazolidinone compounds, LCB01-0371, which reduces mycobacterial survival in macrophage infections, hence confirming the potential of LCB01- 0371 as a therapeutic drug target and suggesting that LCB01-0371 would be a novel candidate for the treatment of infectious diseases caused by mycobacterium tuberculosis.
β-ketoacyl Carrier Protein Synthase Inhibitors Analogs as Potential Antituberculotics
( Da-gyum Lee ),( Noori Lee ),( Tae Yoon Kim ),( Sungweon Ryoo ) 대한결핵 및 호흡기학회 2018 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.126 No.-
Tuberculosis is a significant global health threat, with one-third of the world’s population infected with its causative agent Mycobacterium tuberculosis. Fatty acid biosynthesis is one of the relatively targets in antibacterial drug discovery and most bacterial fatty acid biosynthesis enzymes are essential for viability make this a very attractive antimicrobial drug target. The enzyme β-Ketoacyl-acyl carrier protein synthase (ACPS), contributing in mycolic acids biosynthesis, has been established as promising target of novel antimycobacterial drugs. The ACPS inhibitor analogs have been investigated against Mycobacterium tuberculosis grown either in broth medium or inside macrophages. Our compounds displayed a diversity of action by acting either on extracellular Mycobacterium tuberculosis bacterial growth only, or both intracellularly on infected macrophages as well as extracellularly on bacterial growth with very low toxicity towards host macrophages. Among the eighteen potential ACPS inhibitor analogs identified, YM-12 exhibited the best extracellular antitubercular activity (MIC50 4 ug/ml). In a macrophage model of infection, YM-12 dramatically decreased the number of intracellular Mycobacterium tuberculosis present at 5 days after infection at concentraction of 1.25 ug/ml and 2.5 ug/ml. These results might provide insights into the development of antituberculotics against Mycobacterium. Hence, the mechanism of action of the antituberculous drug on ACPS inhibitors has further investigated.
LEE, YUN-SUN,LEE, DA-GYUM,LEE, JU-YEON,KIM, TAE RYONG,HONG, SOON-SUN,KWON, SUNG WON,KIM, YOU-SUN Spandidos Publications 2013 International journal of oncology Vol.43 No.2
<P>Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent because its cytotoxicity is selective for tumor cells. Despite promising outcomes in clinical trials using this ligand, sustained clinical responses have been impeded because cancer cells acquire resistance to TRAIL-based therapies. Ginseng, a well-known food product consumed globally, has been reported to reduce fatigue and possess antioxidant and antitumor activities. We explored the sensitizing influence of a formulated red ginseng extract (RGE) on TRAIL-derived cell death in hepatocellular carcinoma (HCC) cell lines and the underlying molecular mechanisms responsible for TRAIL sensitization. We found that the RGE promoted TRAIL-derived apoptosis in HepG2, Huh-7 and Hep3B cell lines. We also found that death receptor?5 expression was induced by the RGE and mediated by C/EBP homologous protein (CHOP). shRNA-induced downregulation of CHOP expression effectively suppressed cell death induced by combined treatment with the RGE and TRAIL in the HepG2 cell line, indicating that RGE-related upregulation of the CHOP protein plays an important role in sensitizing TRAIL-derived apoptosis. In summary, we showed that the RGE sensitized human HCC cell lines to TRAIL-derived cell death and could be utilized as a dietary supplement in combination with cancer treatment.</P>
( Jihye Kang ),( Da-gyum Lee ),( Yoohyun Hwang ),( Jiyeon Kim ),( Jihee Jung ),( Donghwan Jang ),( Sungweon Ryoo ) 대한결핵 및 호흡기학회 2021 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.129 No.-
Purpose Anti-tuberculosis drug susceptibility testing (DST) is increasing in importance and demand for treatment. Supply of standardized high-quality DST medium and tuberculosis (TB) specimen titration are key technologies in the DST process. The purpose of this study was to evaluate test method that secures accuracy by taking advantage of the proportion tests. Methods To perform the anti-TB DST, an improved 6-well medium (Middlebrook 7H10 medium) produced in a GMP-qualified place was used. After inoculation in 6-well medium, it was compared with the result of REMA. The concentration of the drug added for the drug susceptibility test was based on the value recommended by WHO. Results The improved 6-well anti-TB DST medium produced in a GMP certified facility is expected to be able to replace the in-house medium used for phenotypic DST. Conclusions It is thought that the medium used for phenotype DST should be produced in a GMP certified facility in order to standardize and high quality. The improved 6-well medium is a meaningful attempt to improve the quality of DST. For the clinical introduction of an improved medium, additional experiments and verification work are required for TB strains with various drug resistance patterns.
Koo, Gi-Bang,Morgan, Michael J,Lee, Da-Gyum,Kim, Woo-Jung,Yoon, Jung-Ho,Koo, Ja Seung,Kim, Seung Il,Kim, Soo Jung,Son, Mi Kwon,Hong, Soon Sun,Levy, Jean M Mulcahy,Pollyea, Daniel A,Jordan, Craig T,Yan Springer Science and Business Media LLC 2015 Cell research Vol.25 No.6
<P>Receptor-interacting protein kinase-3 (RIP3 or RIPK3) is an essential part of the cellular machinery that executes 'programmed' or 'regulated' necrosis. Here we show that programmed necrosis is activated in response to many chemotherapeutic agents and contributes to chemotherapy-induced cell death. However, we show that RIP3 expression is often silenced in cancer cells due to genomic methylation near its transcriptional start site, thus RIP3-dependent activation of MLKL and downstream programmed necrosis during chemotherapeutic death is largely repressed. Nevertheless, treatment with hypomethylating agents restores RIP3 expression, and thereby promotes sensitivity to chemotherapeutics in a RIP3-dependent manner. RIP3 expression is reduced in tumors compared to normal tissue in 85% of breast cancer patients, suggesting that RIP3 deficiency is positively selected during tumor growth/development. Since hypomethylating agents are reasonably well-tolerated in patients, we propose that RIP3-deficient cancer patients may benefit from receiving hypomethylating agents to induce RIP3 expression prior to treatment with conventional chemotherapeutics.</P>