98 results on '"Hyung-Ho Ha"'
Search Results
2. Metastasis‐enhancing protein KITENIN confers temozolomide resistance on glioblastoma with unmethylated MGMT via upregulation of cancer stem cell makers
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Eun‐Jung Ahn, Yeong Jin Kim, Md Rashedunnabi Akanda, Se‐Jeong Oh, Tae‐Young Jung, Shin Jung, Jae‐Hyuk Lee, Sung Sun Kim, Yong Yeon Jeong, Hyung‐Ho Ha, Hoon Hyun, Hangun Kim, Joon Haeng Rhee, Kyung Keun Kim, Kyung‐Hwa Lee, and Kyung‐Sub Moon
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Medicine (General) ,R5-920 - Published
- 2024
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3. KITENIN promotes aerobic glycolysis through PKM2 induction by upregulating the c-Myc/hnRNPs axis in colorectal cancer
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Mücahit Varlı, Sung Jin Kim, Myung-Giun Noh, Yoon Gyoon Kim, Hyung-Ho Ha, Kyung Keun Kim, and Hangun Kim
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KITENIN ,ErbB4 ,MYO1D ,Aerobic glycolysis ,c-Myc ,PKM2 ,Biotechnology ,TP248.13-248.65 ,Biology (General) ,QH301-705.5 ,Biochemistry ,QD415-436 - Abstract
Abstract Purpose The oncoprotein KAI1 C-terminal interacting tetraspanin (KITENIN; vang-like 1) promotes cell metastasis, invasion, and angiogenesis, resulting in shorter survival times in cancer patients. Here, we aimed to determine the effects of KITENIN on the energy metabolism of human colorectal cancer cells. Experimental design The effects of KITENIN on energy metabolism were evaluated using in vitro assays. The GEPIA web tool was used to extrapolate the clinical relevance of KITENIN in cancer cell metabolism. The bioavailability and effect of the disintegrator of KITENIN complex compounds were evaluated by LC–MS, in vivo animal assay. Results KITENIN markedly upregulated the glycolytic proton efflux rate and aerobic glycolysis by increasing the expression of GLUT1, HK2, PKM2, and LDHA. β-catenin, CD44, CyclinD1 and HIF-1A, including c-Myc, were upregulated by KITENIN expression. In addition, KITENIN promoted nuclear PKM2 and PKM2-induced transactivation, which in turn, increased the expression of downstream mediators. This was found to be mediated through an effect of c-Myc on the transcription of hnRNP isoforms and a switch to the M2 isoform of pyruvate kinase, which increased aerobic glycolysis. The disintegration of KITENIN complex by silencing the KITENIN or MYO1D downregulated aerobic glycolysis. The disintegrator of KITENIN complex compound DKC1125 and its optimized form, DKC-C14S, exhibited the inhibition activity of KITENIN-mediated aerobic glycolysis in vitro and in vivo. Conclusions The oncoprotein KITENIN induces PKM2-mediated aerobic glycolysis by upregulating the c-Myc/hnRNPs axis.
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- 2023
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4. Synthesis of coumarin derivatives and investigation of their inhibitory effects on lung cancer cell motility
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Rui Zhou, Young Hyun Yu, Hangun Kim, and Hyung-Ho Ha
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Medicine ,Science - Abstract
Abstract Based on the pharmaceutical potentials of coumarins, which have antitumor activity, we synthesized new coumarin derivatives and evaluated their biological activities. The new coumarin derivatives were chemically synthesized from 4-hydroxycoumarin, and their structures were confirmed by nuclear magnetic resonance data. Ten of the synthesized compounds were investigated for antimetastatic activity against lung carcinoma cells. Several of the tested compounds showed good to mild inhibitory effects on lung cancer cell motility. There were no cytotoxic effects related to the use of these compounds. 4-Hydroxycoumarin derivatives, 4h and 4i, elicited the significant inhibitory effect on lung cancer cell motility by suppressing expression of the epithelial–mesenchymal transition markers N-cadherin, Snail, and Twist.
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- 2022
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5. A new KSRP-binding compound suppresses distant metastasis of colorectal cancer by targeting the oncogenic KITENIN complex
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Jeong A Bae, Woo Kyun Bae, Sung Jin Kim, Yoo-Seung Ko, Keon Young Kim, So-Yeon Park, Young Hyun Yu, Eun Ae Kim, Ik Joo Chung, Hangun Kim, Hyung-Ho Ha, and Kyung Keun Kim
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Colorectal cancer ,KITENIN complex ,KSRP ,Metastasis ,microRNA ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Distant metastasis is the major cause of death in patients with colorectal cancer (CRC). Previously, we identified KITENIN as a metastasis-enhancing gene and suggested that the oncogenic KITENIN complex is involved in metastatic dissemination of KITENIN-overexpressing CRC cells. Here, we attempted to find substances targeting the KITENIN complex and test their ability to suppress distant metastasis of CRC. Methods We screened a small-molecule compound library to find candidate substances suppressing the KITENIN complex in CRC cells. We selected a candidate compound and examined its effects on the KITENIN complex and distant metastasis through in vitro assays, a molecular docking model, and in vivo tumor models. Results Among several compounds, we identified DKC1125 (Disintegrator of KITENIN Complex #1125) as the best candidate. DKC1125 specifically suppressed KITENIN gain of function. After binding KH-type splicing regulatory protein (KSRP), DKC1125 degraded KITENIN and Dvl2 by recruiting RACK1 and miRNA-124, leading to the disintegration of the functional KITENIN–KSRP–RACK1–Dvl2 complex. A computer docking model suggested that DKC1125 specifically interacted with the binding pocket of the fourth KH-domain of KSRP. KITENIN-overexpressing CRC cells deregulated certain microRNAs and were resistant to 5-fluorouracil, oxaliplatin, and cetuximab. DKC1125 restored sensitivity to these drugs by normalizing expression of the deregulated microRNAs, including miRNA-124. DKC1125 effectively suppressed colorectal liver metastasis in a mouse model. Interestingly, the combination of DKC1125 with 5-fluorouracil suppressed metastasis more effectively than either drug alone. Conclusion DKC1125 targets the KITENIN complex and could therefore be used as a novel therapeutic to suppress liver metastasis in CRC expressing high levels of KITENIN.
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- 2021
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6. Topical Delivery of Atraric Acid Derived from Stereocaulon japonicum with Enhanced Skin Permeation and Hair Regrowth Activity for Androgenic Alopecia
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Sultan Pulat, Laxman Subedi, Prashant Pandey, Suresh R. Bhosle, Jae-Seoun Hur, Jung-Hyun Shim, Seung-Sik Cho, Ki-Taek Kim, Hyung-Ho Ha, Hangun Kim, and Jin Woo Park
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atraric acid ,topical delivery ,skin penetration ,dermal papilla cell proliferation ,androgenic alopecia ,hair regrowth ,Pharmacy and materia medica ,RS1-441 - Abstract
Atraric acid (AA) is a phenolic compound isolated from Stereocaulon japonicum that has demonstrated anti-androgen properties and was used to design an alternative formulation for the treatment of alopecia. This new topical formulation was designed using a solvent mixture system composed of ethanol as a volatile vehicle, oleic acid as a permeation enhancer, and water for skin hydration. The ideal topical AA formulation (AA–TF#15) exhibited an 8.77-fold higher human skin flux and a 570% increase in dermal drug deposition, compared to 1% (w/w) AA in ethanol. In addition, compared to other formulations, AA–TF#15 (1% [w/w] AA) activated keratinocytes and human dermal papilla cell proliferation at a concentration of 50 µM AA, which is equivalent to 50 µM minoxidil. Moreover, AA–TF#15 treatment produced a significant increase in hair regrowth by 58.0% and 41.9% compared to the 1% (w/w) minoxidil and oral finasteride (1 mg/kg)-treated mice. In addition, AA–TF#15 showed a higher expression level of aldehyde dehydrogenase 1, β-catenin, cyclin D1, and pyruvate kinase M2 proteins in the skin of AA–TF#15-treated mice compared to that of those treated with minoxidil and oral finasteride. These findings suggest AA–TF#15 is an effective formulation for the treatment of scalp androgenic alopecia.
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- 2023
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7. New strategy for suppressing the growth of lung cancer cells harboring mutations in the ATP‐binding region of EGFR by targeting the molecular motor MYO1D
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Yoo‐Seung Ko, Hyuno Kang, Jeong A Bae, Sung Jin Kim, Nacksung Kim, Ik Joo Chung, Kyung‐Sub Moon, Jin Kyung Rho, Hangun Kim, Hyung‐Ho Ha, In‐Jae Oh, and Kyung Keun Kim
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Medicine (General) ,R5-920 - Published
- 2021
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8. Linking a Gene Cluster to Atranorin, a Major Cortical Substance of Lichens, through Genetic Dereplication and Heterologous Expression
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Wonyong Kim, Rundong Liu, Sunmin Woo, Kyo Bin Kang, Hyun Park, Young Hyun Yu, Hyung-Ho Ha, Seung-Yoon Oh, Ji Ho Yang, Hangun Kim, Sung-Hwan Yun, and Jae-Seoun Hur
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Microbiology ,QR1-502 - Abstract
Lichens play significant roles in ecosystem function and comprise about 20% of all known fungi. Polyketide-derived natural products accumulate in the cortical and medullary layers of lichen thalli, some of which play key roles in protection from biotic and abiotic stresses (e.g., herbivore attacks and UV irradiation).
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- 2021
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9. Development of background-free tame fluorescent probes for intracellular live cell imaging
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Samira Husen Alamudi, Rudrakanta Satapathy, Jihyo Kim, Dongdong Su, Haiyan Ren, Rajkumar Das, Lingna Hu, Enrique Alvarado-Martínez, Jung Yeol Lee, Christian Hoppmann, Eduardo Peña-Cabrera, Hyung-Ho Ha, Hee-Sung Park, Lei Wang, and Young-Tae Chang
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Science - Abstract
The success of a fluorescent dye as a molecular probe to monitor the intracellular activity of biomolecules depends on its physicochemical characteristics. Here, the authors use a predictive model to identify key features that allow them to design cell permeable, background-free fluorescent probes.
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- 2016
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10. Assessment of Degradation Behavior for Acetylsalicylic Acid Using a Plasma in Liquid Process
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Hye-Jin Bang, Heon Lee, Young-Kwon Park, Hyung-Ho Ha, Young Hyun Yu, Byung-Joo Kim, and Sang-Chul Jung
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acetylsalicylic acid ,plasma in liquid phase process ,hydrogen peroxide ,tio2 photocatalyst ,decomposition mechanism ,Chemical technology ,TP1-1185 ,Chemistry ,QD1-999 - Abstract
Acetylsalicylic acid (ASA) is a pharmacologically active compound. In this study, ASA was decomposed effectively using a plasma in liquid phase process with hydrogen peroxide and TiO2 photocatalyst. Increasing the electrical power conditions (frequency, applied voltage, and pulse width) promoted plasma generation, which increased the rate of ASA decomposition. The added hydrogen peroxide increased the rate of ASA degradation, but injecting an excess decreased the degradation rate due to a scavenger effect. Although there was an initial increase in the decomposition efficiency by the addition of TiO2 powder, the addition of an excessive amount inhibited the generation of plasma and decreased the degradation rate. The simultaneous addition of H2O2 and TiO2 powder resulted in the highest degradation efficiency. We suggest that ASA is converted to salicylic acid through demethylation by hydroxyl radicals and is finally mineralized to carbon dioxide and water via 2,4-dihydroxy benzoic acid and low molecular acids.
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- 2019
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11. Mitochondria are physiologically maintained at close to 50 °C.
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Dominique Chrétien, Paule Bénit, Hyung-Ho Ha, Susanne Keipert, Riyad El-Khoury, Young-Tae Chang, Martin Jastroch, Howard T Jacobs, Pierre Rustin, and Malgorzata Rak
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Biology (General) ,QH301-705.5 - Abstract
In endothermic species, heat released as a product of metabolism ensures stable internal temperature throughout the organism, despite varying environmental conditions. Mitochondria are major actors in this thermogenic process. Part of the energy released by the oxidation of respiratory substrates drives ATP synthesis and metabolite transport, but a substantial proportion is released as heat. Using a temperature-sensitive fluorescent probe targeted to mitochondria, we measured mitochondrial temperature in situ under different physiological conditions. At a constant external temperature of 38 °C, mitochondria were more than 10 °C warmer when the respiratory chain (RC) was fully functional, both in human embryonic kidney (HEK) 293 cells and primary skin fibroblasts. This differential was abolished in cells depleted of mitochondrial DNA or treated with respiratory inhibitors but preserved or enhanced by expressing thermogenic enzymes, such as the alternative oxidase or the uncoupling protein 1. The activity of various RC enzymes was maximal at or slightly above 50 °C. In view of their potential consequences, these observations need to be further validated and explored by independent methods. Our study prompts a critical re-examination of the literature on mitochondria.
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- 2018
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12. Antimicrobial Activity of Divaricatic Acid Isolated from the Lichen Evernia mesomorpha against Methicillin-Resistant Staphylococcus aureus
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Jong Min Oh, Yi Jeong Kim, Hyo-Seung Gang, Jin Han, Hyung-Ho Ha, and Hoon Kim
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lichen ,Evernia mesomorpha ,divaricatic acid ,antimicrobial activity ,minimum inhibitory concentration (MIC) ,methicillin-resistant Staphylococcus aureus (MRSA) ,Organic chemistry ,QD241-441 - Abstract
One hundred and seventy seven acetone extracts of lichen and 258 ethyl acetate extracts of cultured lichen-forming fungi (LFF) were screened for antimicrobial activity against Staphylococcus aureus and Enterococcus faecium using a disk diffusion method. Divaricatic acid was isolated from Evernia mesomorpha and identified by LC-MS, 1H-, 13C- and DEPT-NMR. Purified divaricatic acid was effective against Gram + bacteria, such as Bacillus subtilis, Staphylococcus epidermidis, Streptococcus mutans, and Enterococcus faecium, with the minimum inhibitory concentration (MIC) values ranging from 7.0 to 64.0 μg/mL, whereas vancomycin was effective in the MICs ranging from 0.78 to 25.0 μg/mL. Interestingly, the antibacterial activity of divaricatic acid was higher than vancomycin against S. epidermidis and E. faecium, and divaricatic acid was active against Candida albicans. In addition, divaricatic acid was active as vancomycin against S. aureus (3A048; an MRSA). These results suggested that divaricatic acid is a potential antimicrobial agent for the treatment of MRSA infections.
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- 2018
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13. Tumidulin, a Lichen Secondary Metabolite, Decreases the Stemness Potential of Colorectal Cancer Cells
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Yi Yang, Suresh R. Bhosle, Young Hyun Yu, So-Yeon Park, Rui Zhou, İsa Taş, Chathurika D. B. Gamage, Kyung Keun Kim, Iris Pereira, Jae-Seoun Hur, Hyung-Ho Ha, and Hangun Kim
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lichen ,secondary metabolites ,tumidulin ,stemness potential ,colorectal cancer cells ,oncogene ,transcriptional regulation ,Organic chemistry ,QD241-441 - Abstract
Lichens produce various unique chemicals that are used in the pharmaceutical industry. To screen for novel lichen secondary metabolites that inhibit the stemness potential of colorectal cancer cells, we tested acetone extracts of 11 lichen samples collected in Chile. Tumidulin, isolated from Niebla sp., reduced spheroid formation in CSC221, DLD1, and HT29 cells. In addition, mRNA expressions and protein levels of cancer stem markers aldehyde dehydrogenase-1 (ALDH1), cluster of differentiation 133 (CD133), CD44, Lgr5, and Musashi-1 were reduced after tumidulin treatment. Tumidulin decreased the transcriptional activity of the glioma-associated oncogene homolog zinc finger protein (Gli) promoter in reporter assays, and western blotting confirmed decreased Gli1, Gli2, and Smoothened (SMO) protein levels. Moreover, the tumidulin activity was not observed in the presence of Gli and SMO inhibitors. Together, these results demonstrate for the first time that tumidulin is a potent inhibitor of colorectal cancer cell stemness.
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- 2018
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14. Inhibitory Activity of (+)-Usnic Acid against Non-Small Cell Lung Cancer Cell Motility.
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Yi Yang, Thanh Thi Nguyen, Min-Hye Jeong, Florin Crişan, Young Hyun Yu, Hyung-Ho Ha, Kyung Hee Choi, Hye Gwang Jeong, Tae Cheon Jeong, Kwang Youl Lee, Kyung Keun Kim, Jae-Seoun Hur, and Hangun Kim
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Medicine ,Science - Abstract
Lichens are symbiotic organisms that produce various unique chemicals that can be used for pharmaceutical purposes. With the aim of screening new anti-cancer agents that inhibit cancer cell motility, we tested the inhibitory activity of seven lichen species collected from the Romanian Carpathian Mountains against migration and invasion of human lung cancer cells and further investigated the molecular mechanisms underlying their anti-metastatic activity. Among them, Alectoria samentosa, Flavocetraria nivalis, Alectoria ochroleuca, and Usnea florida showed significant inhibitory activity against motility of human lung cancer cells. HPLC results showed that usnic acid is the main compound in these lichens, and (+)-usnic acid showed similar inhibitory activity that crude extract have. Mechanistically, β-catenin-mediated TOPFLASH activity and KITENIN-mediated AP-1 activity were decreased by (+)-usnic acid treatment in a dose-dependent manner. The quantitative real-time PCR data showed that (+)-usnic acid decreased the mRNA level of CD44, Cyclin D1 and c-myc, which are the downstream target genes of both β-catenin/LEF and c-jun/AP-1. Also, Rac1 and RhoA activities were decreased by treatment with (+)-usnic acid. Interestingly, higher inhibitory activity for cell invasion was observed when cells were treated with (+)-usnic acid and cetuximab. These results implied that (+)-usnic acid might have potential activity in inhibition of cancer cell metastasis, and (+)-usnic acid could be used for anti-cancer therapy with a distinct mechanisms of action.
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- 2016
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15. Glycoprotein 90K Promotes E-Cadherin Degradation in a Cell Density-Dependent Manner via Dissociation of E-Cadherin–p120-Catenin Complex
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So-Yeon Park, Somy Yoon, Eun Gene Sun, Rui Zhou, Jeong A. Bae, Young-Woo Seo, Jung-Il Chae, Man-Jeong Paik, Hyung-Ho Ha, Hangun Kim, and Kyung Keun Kim
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90K glycoprotein ,LGALS3BP ,Mac-2BP ,E-cadherin ,p120-catenin ,adherens junction ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Glycoprotein 90K (also known as LGALS3BP or Mac-2BP) is a tumor-associated protein, and high 90K levels are associated with poor prognosis in some cancers. To clarify the role of 90K as an indicator for poor prognosis and metastasis in epithelial cancers, the present study investigated the effect of 90K on an adherens junctional protein, E-cadherin, which is frequently absent or downregulated in human epithelial cancers. Treatment of certain cancer cells with 90K significantly reduced E-cadherin levels in a cell-population-dependent manner, and these cells showed decreases in cell adhesion and increases in invasive cell motility. Mechanistically, 90K-induced E-cadherin downregulation occurred via ubiquitination-mediated proteasomal degradation. 90K interacted with the E-cadherin–p120-catenin complex and induced its dissociation, altering the phosphorylation status of p120-catenin, whereas it did not associate with β-catenin. In subconfluent cells, 90K decreased membrane-localized p120-catenin and the membrane fraction of the p120-catenin. Particularly, 90K-induced E-cadherin downregulation was diminished in p120-catenin knocked-down cells. Taken together, 90K upregulation promotes the dissociation of the E-cadherin–p120-catenin complex, leading to E-cadherin proteasomal degradation, and thereby destabilizing adherens junctions in less confluent tumor cells. Our results provide a potential mechanism to explain the poor prognosis of cancer patients with high serum 90K levels.
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- 2017
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16. Lichen Secondary Metabolite, Physciosporin, Inhibits Lung Cancer Cell Motility.
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Yi Yang, So-Yeon Park, Thanh Thi Nguyen, Young Hyun Yu, Tru Van Nguyen, Eun Gene Sun, Jayalal Udeni, Min-Hye Jeong, Iris Pereira, Cheol Moon, Hyung-Ho Ha, Kyung Keun Kim, Jae-Seoun Hur, and Hangun Kim
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Medicine ,Science - Abstract
Lichens produce various unique chemicals that can be used for pharmaceutical purposes. To screen for novel lichen secondary metabolites showing inhibitory activity against lung cancer cell motility, we tested acetone extracts of 13 lichen samples collected in Chile. Physciosporin, isolated from Pseudocyphellaria coriacea (Hook f. & Taylor) D.J. Galloway & P. James, was identified as an effective compound and showed significant inhibitory activity in migration and invasion assays against human lung cancer cells. Physciosporin treatment reduced both protein and mRNA levels of N-cadherin with concomitant decreases in the levels of epithelial-mesenchymal transition markers such as snail and twist. Physciosporin also suppressed KITENIN (KAI1 C-terminal interacting tetraspanin)-mediated AP-1 activity in both the absence and presence of epidermal growth factor stimulation. Quantitative real-time PCR analysis showed that the expression of the metastasis suppressor gene, KAI1, was increased while that of the metastasis enhancer gene, KITENIN, was dramatically decreased by physciosporin. Particularly, the activity of 3'-untranslated region of KITENIN was decreased by physciosporin. Moreover, Cdc42 and Rac1 activities were decreased by physciosporin. These results demonstrated that the lichen secondary metabolite, physciosporin, inhibits lung cancer cell motility through novel mechanisms of action.
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- 2015
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17. Assessing the photocatalytic activity of europium doped TiO2 using liquid phase plasma process on acetylsalicylic acid
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Sang-Chul Jung, Hye-Jin Bang, Hyung-Ho Ha, Young-Kwon Park, Sun-Jae Kim, Young Hyun Yu, and Heon Lee
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Materials science ,Precipitation (chemistry) ,Inorganic chemistry ,Oxide ,chemistry.chemical_element ,02 engineering and technology ,General Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Catalysis ,0104 chemical sciences ,chemistry.chemical_compound ,symbols.namesake ,X-ray photoelectron spectroscopy ,chemistry ,symbols ,Photocatalysis ,0210 nano-technology ,Europium ,Raman spectroscopy ,Visible spectrum - Abstract
In this study, europium (Eu) was precipitated in TiO2 powder using liquid phase plasma (LPP) process to prepare a photocatalyst with higher activity, even in the visible light range. Eu was uniformly deposited on the surface of TiO2 by the LPP method. It was observed that the amount of Eu precipitated on the TiO2 surface increased with increasing precursor concentration. XPS and EDS analysis showed that Eu was precipitated as europium oxide. The precipitation of Eu shifted the position of the Raman peak to a higher wavelength; with higher Eu content, the band gap energy decreased. Particularly, the photocatalytic efficiency of the Eu doped TiO2 photocatalyst (EDTP) in the visible light source was much higher than that of bare TiO2, and with higher Eu content, the photocatalytic activity was improved. Acetylsalicylic acid was attacked by HO∙ produced on the EDTP’s surface and assumed to be finally mineralized to H2O and CO2 via two decomposition pathways, namely, decarboxylation and deacetylation.
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- 2022
18. Target identification of mouse stem cell probe CDy1 as ALDH2 and Abcb1b through live-cell affinity-matrix and ABC CRISPRa library†
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Young-Hyun Go, Naoki Miyamoto, Xuezhi Bi, Larissa Miasiro Ciaramicoli, Heon Seok Kim, Haw-Young Kwon, Young Hyun Yu, Nam-Young Kang, Hyung-Ho Ha, Jin-Soo Kim, Seong-Wook Yun, Beomsue Kim, Young-Tae Chang, and Hyuk-Jin Cha
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Mechanism (biology) ,Regeneration (biology) ,Cell ,ATP-binding cassette transporter ,Biology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Biochemistry ,Embryonic stem cell ,Cell biology ,Chemistry ,medicine.anatomical_structure ,Chemistry (miscellaneous) ,medicine ,Identification (biology) ,Stem cell ,Molecular Biology ,Reprogramming - Abstract
CDy1 is a powerful tool to distingusih embryonic stem cells for reprogramming studies and regeneration medicine. However, the stem cell selectivity mechanism of CDy1 has not been fully understood. Here, we report ALDH2 and ABCB1 as the molecular targets of CDy1, elucidated by live-cell affinity-matrix and ABC transporter CRISPRa library screening. The two unique orthogonal mechanisms provide the potential of multi-demensional cellular distinction of specific cell types., CDy1 is a powerful tool to distingusih embryonic stem cells for reprogramming studies and regeneration medicine.
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- 2021
19. Abstract B018: Suppression of distant metastasis of colorectal cancer by small molecule compound through targeting the oncogenic KITENIN complex
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Sung Jin Kim, Jeong A. Bae, Yoon Gyoon Kim, Eun Ae Kim, Hyung-Ho Ha, Hangun Kim, and Kyung Keun Kim
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Cancer Research ,Oncology - Abstract
Distant metastasis is a major reason for cancer-related death. We previously identified KITENIN (KAI1 C-terminal interacting tetraspanin, Vangl1), a gene encoding a membrane-associated protein, as a metastasis-enhancing gene. The oncogenic KITENIN complex is found to be involved in metastatic dissemination of KITENIN-overexpressing colorectal cancer (CRC) cells and also plays an important role in colorectal carcinogenesis within an APC-loss environment, all of which proposing that the KITENIN complex represents a molecular target for therapeutics aimed at blocking the malignant progression of CRC. To develop novel anti-metastatic agents, we sought to identify therapeutics capable of breaking down the oncogenic KITENIN complex in CRC cells and searched for low-molecular weight compounds that break down the complex, thereby shutting off its oncogenic signals. We then tested the effectiveness of the identified substances in suppressing colorectal liver metastasis (CLM). We found a compound that specifically blocked oncogenic signals from the functional KITENIN complex in CRC cells and renamed it as DKC (Disintegrator of KITENIN Complex) compound. DKC compound bound the KH-type splicing regulatory protein (KSRP), a downstream factor and stabilizer of the functional KITENIN complex, and specifically suppressed invasiveness of CRC cells expressing higher levels of KITENIN. After treatment with DKC compound, RACK1 and microRNA-124 were recruited, resulting in removal of KITENIN from the complex followed by its degradation. DKC suppressed hepatic metastasis effectively in a mouse model of CLM with higher KITENIN. Intriguingly, DKC compound combined with 5-fluorouracil resulted in an enhanced therapeutic effect. Thus, disintegration of the functional KITENIN complex following DKC treatment led to alteration of the specific cellular context induced by the KITENIN complex. Among the synthetic DKC analogues, we selected the one as the optimized leading compound. A docking model study suggested that the interaction between the optimized leading compound with KSRP occurs via insertion of the compound into the binding pocket of the fourth KH-domain and pharmacokinectic studies showed that the favorable blood level was maintained after oral or intravenous administration in rat. Overall, DKC compound specifically blocked oncogenic signals from the functional KITENIN complex in CRC cells with higher KITENIN and suppressed CLM by targeting the KITENIN complex. Our results suggest that a combination regimen with DKC compound could be used more effectively to treat distant metastasis and chemoresistance in CRC patients with high KITENIN expression. Citation Format: Sung Jin Kim, Jeong A. Bae, Yoon Gyoon Kim, Eun Ae Kim, Hyung-Ho Ha, Hangun Kim, Kyung Keun Kim. Suppression of distant metastasis of colorectal cancer by small molecule compound through targeting the oncogenic KITENIN complex [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B018.
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- 2023
20. Fabrication of Yb-doped TiO2 using liquid phase plasma process and its photocatalytic degradation activity of naproxen
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Young-Kwon Park, Hyung-Ho Ha, Hye-Jin Bang, Sun-Jae Kim, Hangun Kim, Heon Lee, Sang-Chul Jung, and Young Hyun Yu
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Ytterbium ,Materials science ,Decarboxylation ,Band gap ,020502 materials ,Mechanical Engineering ,Radical ,Doping ,Nanoparticle ,chemistry.chemical_element ,02 engineering and technology ,Decomposition ,0205 materials engineering ,chemistry ,Mechanics of Materials ,General Materials Science ,Nuclear chemistry ,Visible spectrum - Abstract
Photocatalysts responding to visible light were prepared by doping ytterbium (Yb) to TiO2 powder by LPP method. Yb2O3 nanoparticles were uniformly precipitated on the surface of TiO2 powder, and when the precursor concentration was increased, the precipitated Yb2O3 nanoparticles increased. The precipitated Yb element lowered the band gap energy of Yb-doped TiO2 photocatalyst (YTP) by 0.07 to 0.14 eV compared to bare TiO2. YTPs degraded naproxen (NPX) better than bare TiO2, especially under blue LED light (maximum wavelength 470 nm), and YTP containing higher Yb elements showed higher decomposition activity. NPX was decomposed into CO2 and H2O by decarboxylation and demethylation by hydroxyl radicals generated from TiO2 photocatalysts, suggesting a degradation pathway based on the three intermediates detected by LC/MS analysis.
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- 2020
21. New strategy for suppressing the growth of lung cancer cells harboring mutations in the ATP-binding region of EGFR by targeting the molecular motor MYO1D
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In-Jae Oh, Kyung Keun Kim, Jin Kyung Rho, Hangun Kim, Sung Jin Kim, Jeong A Bae, Nacksung Kim, Hyung-Ho Ha, Yoo-Seung Ko, Hyuno Kang, Kyung-Sub Moon, and Ik Joo Chung
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Medicine (General) ,Lung Neoplasms ,Medicine (miscellaneous) ,Antineoplastic Agents ,In Vitro Techniques ,Myosins ,Afatinib ,Letter to Editor ,Mice ,R5-920 ,Carcinoma, Non-Small-Cell Lung ,Molecular motor ,Medicine ,Animals ,Lung cancer ,Acrylamides ,Aniline Compounds ,business.industry ,Gefitinib ,medicine.disease ,ErbB Receptors ,Disease Models, Animal ,Mutation ,Cancer research ,Molecular Medicine ,business - Published
- 2021
22. Linking a Gene Cluster to Atranorin, a Major Cortical Substance of Lichens, through Genetic Dereplication and Heterologous Expression
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Rundong Liu, Sunmin Woo, Hyung-Ho Ha, Ji Ho Yang, Young Hyun Yu, Wonyong Kim, Jae-Seoun Hur, Hyun Park, Kyo Bin Kang, Sung-Hwan Yun, Hangun Kim, and Seung-Yoon Oh
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Lichens ,Gene Expression ,lichen ,01 natural sciences ,Orsellinic acid ,Microbiology ,Fungal Proteins ,Cladonia ,03 medical and health sciences ,chemistry.chemical_compound ,Polyketide ,Ascomycota ,atranorin ,stomatognathic system ,Virology ,Polyketide synthase ,Gene cluster ,Hydroxybenzoates ,skin and connective tissue diseases ,Lichen ,Phylogeny ,030304 developmental biology ,Genetics ,secondary metabolism ,0303 health sciences ,biology ,integumentary system ,010405 organic chemistry ,Depsidone ,Editor's Pick ,biology.organism_classification ,QR1-502 ,Biosynthetic Pathways ,0104 chemical sciences ,stomatognathic diseases ,chemistry ,Multigene Family ,Polyketides ,biology.protein ,Polyketide Synthases ,Research Article ,Depside - Abstract
The depside and depsidone series compounds of polyketide origin accumulate in the cortical or medullary layers of lichen thalli. Despite the taxonomic and ecological significance of lichen chemistry and its pharmaceutical potentials, there has been no single piece of genetic evidence linking biosynthetic genes to lichen substances. Thus, we systematically analyzed lichen polyketide synthases (PKSs) for categorization and identification of the biosynthetic gene cluster (BGC) involved in depside/depsidone production. Our in-depth analysis of the interspecies PKS diversity in the genus Cladonia and a related Antarctic lichen, Stereocaulon alpinum, identified 45 BGC families, linking lichen PKSs to 15 previously characterized PKSs in nonlichenized fungi. Among these, we identified highly syntenic BGCs found exclusively in lichens producing atranorin (a depside). Heterologous expression of the putative atranorin PKS gene (coined atr1) yielded 4-O-demethylbarbatic acid, found in many lichens as a precursor compound, indicating an intermolecular cross-linking activity of Atr1 for depside formation. Subsequent introductions of tailoring enzymes into the heterologous host yielded atranorin, one of the most common cortical substances of macrolichens. Phylogenetic analysis of fungal PKS revealed that the Atr1 is in a novel PKS clade that included two conserved lichen-specific PKS families likely involved in biosynthesis of depsides and depsidones. Here, we provide a comprehensive catalog of PKS families of the genus Cladonia and functionally characterize a biosynthetic gene cluster from lichens, establishing a cornerstone for studying the genetics and chemical evolution of diverse lichen substances. IMPORTANCE Lichens play significant roles in ecosystem function and comprise about 20% of all known fungi. Polyketide-derived natural products accumulate in the cortical and medullary layers of lichen thalli, some of which play key roles in protection from biotic and abiotic stresses (e.g., herbivore attacks and UV irradiation). To date, however, no single lichen product has been linked to respective biosynthetic genes with genetic evidence. Here, we identified a gene cluster family responsible for biosynthesis of atranorin, a cortical substance found in diverse lichen species, by categorizing lichen polyketide synthase and reconstructing the atranorin biosynthetic pathway in a heterologous host. This study will help elucidate lichen secondary metabolism, harnessing the lichen's chemical diversity, hitherto obscured due to limited genetic information on lichens.
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- 2021
23. Differences in the molecular signatures of mucosal-associated invariant T cells and conventional T cells
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Dae Ho Lee, Hyung-Ho Ha, Daeui Park, Hwan Jung Lim, Hong Gi Kim, Kang-Seo Park, Seong-Jun Park, Tamina Park, Miok Kim, and Chang-Hoon Lee
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0301 basic medicine ,Receptors, Antigen, T-Cell, alpha-beta ,Cell ,lcsh:Medicine ,Blood Donors ,Mucosal associated invariant T cell ,Biology ,Mucosal-Associated Invariant T Cells ,Article ,Gene regulatory networks ,Arthritis, Rheumatoid ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,Immunogenetics ,medicine ,T-Cell Receptor Alpha Chain ,Humans ,RNA-Seq ,lcsh:Science ,Gene ,Multidisciplinary ,lcsh:R ,RNA ,Molecular biology ,Phenotype ,Killer Cells, Natural ,030104 developmental biology ,medicine.anatomical_structure ,Th17 Cells ,lcsh:Q ,Signal transduction ,030217 neurology & neurosurgery ,NK Cell Lectin-Like Receptor Subfamily B ,Transcription Factors - Abstract
Mucosal-associated invariant T (MAIT) cells exhibit different characteristics from those of TCRα7.2− conventional T cells. They play important roles in various inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. MAIT cells express a single T cell receptor alpha chain, TCRα7.2 segment associated with Jα33 and CDR3 with fixed length, which recognizes bacteria-derived vitamin B metabolites. However, the characteristics of MAIT cells and TCRα7.2+ CD161− T cells have never been compared. Here, we performed RNA sequencing to compare the properties of MAIT cells, TCRα7.2− conventional T cells and TCRα7.2+ CD161− T cells. Genome-wide transcriptomes of MAIT cells, TCRα7.2− conventional T cells, and TCRα7.2+ CD161− T cells were compared and analyzed using causal network analysis. This is the first report comparing the transcriptomes of MAIT cells, TCRα7.2− conventional T cells and TCRα7.2+ CD161− T cells. We also identified the predominant signaling pathways of MAIT cells, which differed from those of TCRα7.2− conventional T cells and TCRα7.2+ CD161− T cells, through a gene set enrichment test and upstream regulator analysis and identified the genes responsible for the characteristic MAIT cell phenotypes. Our study advances the complete understanding of MAIT biology.
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- 2019
24. Physciosporin suppresses the proliferation, motility and tumourigenesis of colorectal cancer cells
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Hyung-Ho Ha, Yong Jae Choi, Chathurika D.B. Gamage, So-Yeon Park, Rui Zhou, Young Hyun Yu, Kyung-Sub Moon, Tru Van Nguyen, İsa Taş, Kyung Keun Kim, Ji-Yoon Lee, Yi Yang, Hangun Kim, Sang Kyum Kim, Jin Han, and Jae-Seoun Hur
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Male ,Epithelial-Mesenchymal Transition ,Lichens ,Cell Survival ,Pharmaceutical Science ,Motility ,Antineoplastic Agents ,Apoptosis ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Cytotoxic T cell ,MTT assay ,Viability assay ,Epithelial–mesenchymal transition ,beta Catenin ,Cell Proliferation ,030304 developmental biology ,Pharmacology ,Mice, Inbred BALB C ,0303 health sciences ,Dose-Response Relationship, Drug ,Chemistry ,Xenograft Model Antitumor Assays ,In vitro ,Gene Expression Regulation, Neoplastic ,Cell Transformation, Neoplastic ,Complementary and alternative medicine ,Cell culture ,030220 oncology & carcinogenesis ,Oxepins ,Cancer research ,Molecular Medicine ,Drug Screening Assays, Antitumor ,Colorectal Neoplasms - Abstract
Background Lichens, which represent symbiotic associations of fungi and algae, are potential sources of numerous natural products. Physciosporin (PHY) is a potent secondary metabolite found in lichens and was recently reported to inhibit the motility of lung cancer cells via novel mechanisms. Purpose The present study investigated the anticancer potential of PHY on colorectal cancer (CRC) cells. Methods PHY was isolated from lichen extract by preparative TLC. The effect of PHY on cell viability, motility and tumourigenicity was elucidated by MTT assay, hoechst staining, flow cytometric analysis, transwell invasion and migration assay, soft agar colony formation assay, Western blotting, qRT-PCR and PCR array in vitro as well as tumorigenicity study in vivo. Results PHY decreased the viability of various CRC cell lines (Caco2, CT26, DLD1, HCT116 and SW620). Moreover, PHY elicited cytotoxic effects by inducing apoptosis at toxic concentrations. At non-toxic concentrations, PHY dose-dependently suppressed the invasion, migration and colony formation of CRC cells. PHY inhibited the motility of CRC cells by suppressing epithelial-mesenchymal transition and downregulating actin-based motility markers. In addition, PHY downregulated β-catenin and its downstream target genes cyclin-D1 and c-Myc. Moreover, PHY modulated KAI1 C-terminal-interacting tetraspanin and KAI1 expression, and downregulated the downstream transcription factors c-jun and c-fos. Finally, PHY administration showed considerable bioavailability and effectively decreased the growth of CRC xenografts in mice without causing toxicity. Conclusion PHY suppresses the growth and motility of CRC cells via novel mechanisms.
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- 2019
25. Potassium usnate, a water-soluble usnic acid salt, shows enhanced bioavailability and inhibits invasion and metastasis in colorectal cancer
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Man-Jeong Paik, Ik Joo Chung, Chathurika D.B. Gamage, Kyung Keun Kim, Myong-Suk Park, Woo Kyun Bae, Yong Jae Choi, Ji-Yoon Lee, İsa Taş, Jae-Seoun Hur, Jae Hyuk Lee, Hangun Kim, Yi Yang, Rui Zhou, Young Hyun Yu, Kyung-Hwa Lee, Hyung-Ho Ha, So-Yeon Park, and Sang Kyum Kim
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0301 basic medicine ,Male ,Epithelial-Mesenchymal Transition ,Slug ,Colorectal cancer ,Administration, Oral ,Biological Availability ,lcsh:Medicine ,Antineoplastic Agents ,Selenic Acid ,Article ,Metastasis ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,In vivo ,Oral administration ,Cell Movement ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,lcsh:Science ,Benzofurans ,Cell Proliferation ,Multidisciplinary ,biology ,lcsh:R ,Usnic acid ,medicine.disease ,biology.organism_classification ,In vitro ,Bioavailability ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,030104 developmental biology ,Treatment Outcome ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Potassium ,lcsh:Q ,Drug Screening Assays, Antitumor ,Colorectal Neoplasms - Abstract
Usnic acid (UA), a lichen secondary substance, has considerable anticancer activity in vitro, whereas its effect in vivo is limited. Here, potassium usnate (KU) was prepared by the salinization of UA to enhance its water solubility. KU showed increased bioavailability compared with UA in the tumor, liver, and plasma of a CT26 syngeneic mouse tumor xenograft model after oral administration, as determined by LC-MS/MS analysis. KU exhibited potent anticancer effects on colorectal cancer cells and inhibited liver metastasis in an orthotopic murine colorectal cancer model. KU treatment downregulated the epithelial-mesenchymal markers Twist, Snail, and Slug and the metastasis-related genes CAPN1, CDC42, CFL1, IGF1, WASF1, and WASL in cells and tumor tissues. The present results suggest the potential application of the water-soluble form of UA, KU, in anticancer therapy.
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- 2018
26. A heptamethine cyanine dye serves as a potential marker for myeloid-derived suppressor cells
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Young-Suk, Cho, Manh-Hung, Do, Hien, Duong Thanh, Changjong, Moon, Kwonseop, Kim, Sang-Hee, Cho, Hangun, Kim, Hyung-Ho, Ha, and Chaeyong, Jung
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Original Article - Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with inhibitory effects on T cell-mediated immune response. MDSCs accumulate under many pathological conditions, including cancers, to avoid anticancer immunity. Unlike mouse MDSCs, common specific surface markers for human MDSCs are not clearly defined, mainly due to the complexity of MDSC subsets. In this study, we investigate specific responses of the infrared dye MHI-148 to MDSCs. Mice bearing 4T1 breast cancer cells were established, and splenocytes were isolated. Flow cytometric analyses demonstrated that MHI-148 was reactive to over 80% of MDSC-specific cells manifesting CD11b(+)/Gr-1(+) acquired from both tumor-bearing mice and naive mice. Cells sorted positive for either CD11b/Gr-1 or MHI-148 were also identical to their counterparts (99.7% and 97.7%, respectively). MHI-148, however, was not reactive to lymphocyte or monocyte populations. To determine whether MHI-148-reactive cells exert inhibitory effects on T cell proliferation, an EdU-based T cell assay was performed. MHI-148 reactive cells significantly reduced T cell proliferation with increased arginase activity and nitrite production. In an attempt to test MHI-148 as a marker for human MDSCs, MHI-148 was specifically reactive to CD11b(+)/CD33(+)/CD14(-) granulocytic MDSCs acquired from selected cancer patients. This study demonstrates that the near-infrared dye MHI-148 specifically reacts to mouse splenocytes with known MDSC-specific markers that have T cell suppressive functions. The dye also selectively binds to a subpopulation of immature myeloid cells acquired from cancer patients. While it is not clear how MHI-148 specifically stains MDSCs, this dye can be a novel tool to detect MDSCs and to predict the prognosis of human cancer patients.
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- 2021
27. Transcriptome analysis upon potassium usnate exposure reveals ATF3-induced apoptosis in human gastric and colon cancer cells
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Hyung-Ho Ha, Kyung Hyun Yoo, Sumin Oh, Sang-Hee Cho, Myong-Suk Park, Ik-Joo Chung, Hangun Kim, Woo Kyun Bae, and D.E. Kim
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Pharmaceutical Science ,Apoptosis ,Transcriptome ,Mice ,Western blot ,Stomach Neoplasms ,Cell Line, Tumor ,Drug Discovery ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Viability assay ,Benzofurans ,Pharmacology ,Gene knockdown ,Activating Transcription Factor 3 ,medicine.diagnostic_test ,Chemistry ,Gene Expression Profiling ,Endoplasmic Reticulum Stress ,Complementary and alternative medicine ,Colonic Neoplasms ,Cancer research ,Potassium ,Molecular Medicine ,GADD45A ,Chromatin immunoprecipitation - Abstract
Background Potassium usnate (KU), a water-soluble form of usnic acid, shows anticancer activity. However, the underlying mechanisms have not been fully elucidated. Purpose We aimed to identify the pathways involved in anticancer effects of KU in human gastric cancer (GC) and colorectal cancer (CRC) cells using RNA-sequencing (RNA-seq) based transcriptome analysis. Study Design We analyzed the cytotoxic effects of KU to identify the common molecular events in GC and CRC cells upon KU exposure using unbiased approaches. Methods Cell viability assays and western blot experiments were used to examine apoptotic changes, cell cycle arrest, and endoplasmic reticulum (ER) stress-induced cellular responses in KU-treated cells. Total RNA from KU-treated human GC and CRC cells was prepared for RNA-seq analysis. Gene ontology term and gene set enrichment analyses were used to identify the key mediators of the cytotoxic effects of KU. The expression of ER stress-induced apoptotic markers was evaluated using quantitative reverse-transcription PCR and western blot analysis. Chromatin immunoprecipitation assays for ATF3 and H3K27ac, and ATF3 knockdown were employed to verify the underlying molecular mechanisms. The inhibitory effect of KU on tumor growth in vivo was validated with metastatic tumor nodule formations in a mouse liver model. Results KU exerted cytotoxicity in human GC and CRC cells through the activation of the ER stress-induced apoptotic pathway. KU stimulated ATF3 expression, an important mediator of molecular events of apoptosis. ATF3 binds to the promoter region of ATF3, CHOP, GADD34, GADD45A, DR5, and PUMA genes and subsequently promoted apoptotic events. Knockdown of ATF3 significantly reduced the expression of ATF3 target genes and the cytotoxic effects of KU. The intraperitoneal injection of KU induced ATF3 and the apoptosis of implanted colon cancer cells, resulting in reduced metastatic tumor growth in the mouse livers. Conclusion KU exerts cytotoxic effects in human GC and CRC cells by triggering ER stress-induced apoptosis via an ATF3 dependent pathway.
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- 2021
28. The photocatalytic destruction of cimetidine using microwave-assisted TiO
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Young-Kwon, Park, Hyung-Ho, Ha, Young Hyun, Yu, Byung-Joo, Kim, Hye-Jin, Bang, Heon, Lee, and Sang-Chul, Jung
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Titanium ,Ultraviolet Rays ,Hydrogen-Ion Concentration ,Cimetidine ,Microwaves ,Photochemical Processes ,Catalysis ,Water Pollutants, Chemical - Abstract
Microwave/Microwave discharge electrodeless lamp/Dissolved Oxygen/TiO
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- 2020
29. Physciosporin suppresses mitochondrial respiration, aerobic glycolysis, and tumorigenesis in breast cancer
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Mücahit Varlı, Yi Yang, Jin Han, Hyung-Ho Ha, So-Yeon Park, Yeseon Son, Hangun Kim, Dahye Kwak, Kyung-Sub Moon, Jae-Seoun Hur, İsa Taş, Kyung-Hwa Lee, Rui Zhou, Young Hyun Yu, Chathurika D.B. Gamage, and Sultan Pulat
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Pharmaceutical Science ,Apoptosis ,Breast Neoplasms ,Triple Negative Breast Neoplasms ,PKM2 ,medicine.disease_cause ,Mice ,Cell Line, Tumor ,Drug Discovery ,medicine ,Animals ,Humans ,MTT assay ,Viability assay ,Clonogenic assay ,Cell Proliferation ,Pharmacology ,Cell growth ,Chemistry ,Cell Transformation, Neoplastic ,Complementary and alternative medicine ,Anaerobic glycolysis ,Oxepins ,Cancer cell ,Cancer research ,Molecular Medicine ,Female ,Carcinogenesis ,Glycolysis - Abstract
Background Physciosporin (PHY) is one of the potent anticancer lichen compound. Recently, PHY was shown to suppress colorectal cancer cell proliferation, motility, and tumorigenesis through novel mechanisms of action. Purpose We investigated the effects of PHY on energy metabolism and tumorigenicity of the human breast cancer (BC) cells MCF-7 (estrogen and progesterone positive BC) and MDA-MB-231 (triple negative BC). Methods The anticancer effect of PHY on cell viability, motility, cancer metabolism and tumorigenicity was evaluated by MTT assay, migration assay, clonogenic assay, anchorage-independent colony formation assay, glycolytic and mitochondrial metabolism analysis, qRT-PCR, flow cytometric analysis, Western blotting, immunohistochemistry in vitro; and by tumorigenicity study with orthotopic breast cancer xenograft model in vivo. Results PHY markedly inhibited BC cell viability. Cell-cycle profiling and Annexin V–FITC/PI double staining showed that a toxic dosage of PHY triggered apoptosis in BC cell lines by regulating the B-cell lymphoma-2 (Bcl-2) family proteins and the activity of caspase pathway. At non-toxic concentrations, PHY potently decreased migration, proliferation, and tumorigenesis of BC cells in vitro. Metabolic studies revealed that PHY treatment significantly reduced the bioenergetic profile by decreasing respiration, ATP production, and glycolysis capacity. In addition, PHY significantly altered the levels of mitochondrial (PGC-1α) and glycolysis (GLUT1, HK2 and PKM2) markers, and downregulated transcriptional regulators involved in cancer cell metabolism, including β-catenin, c-Myc, HIF-1α, and NF-κB. An orthotopic implantation mouse model of BC confirmed that PHY treatment suppressed BC growth in vivo and target genes were consistently suppressed in tumor specimens. Conclusion The findings from our in vitro as well as in vivo studies exhibit that PHY suppresses energy metabolism as well as tumorigenesis in BC. Especially, PHY represents a promising therapeutic effect against hormone-insensitive BC (triple negative) by targeting energy metabolism.
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- 2021
30. A Near-Infrared Probe Tracks and Treats Lung Tumor Initiating Cells by Targeting HMOX2
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Hyung-Ho Ha, Sungjin Park, Jungyeol Lee, Xiao Liu, Nam-Young Kang, Jong-Jin Kim, Seong Soon Kim, Zhenxun Wang, Lu Wang, Haw-Young Kwon, Yong-An Lee, So Young Choi, Seong Cheol Hong, Animesh Samanta, Myung Ae Bae, Young Hyun Yu, Wai Leong Tam, Jun-Seok Lee, Young-Tae Chang, Junyoung Kim, Bing Lim, Jia Hui Jane Lee, Beomsue Kim, and Dongdong Su
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congenital, hereditary, and neonatal diseases and abnormalities ,Lung Neoplasms ,HMOX2 ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Catalysis ,Metastasis ,Mice ,Colloid and Surface Chemistry ,mental disorders ,medicine ,Animals ,Humans ,Fluorescent Dyes ,Spectroscopy, Near-Infrared ,biology ,Chemistry ,Cancer ,General Chemistry ,medicine.disease ,Ligand (biochemistry) ,Small molecule ,Xenograft Model Antitumor Assays ,nervous system diseases ,0104 chemical sciences ,body regions ,Heme oxygenase ,Survival Rate ,Heme Oxygenase (Decyclizing) ,Cancer research ,biology.protein ,Neoplastic Stem Cells ,Biomarker (medicine) ,human activities ,Preclinical imaging - Abstract
Tumor initiating cells (TIC) are resistant to conventional anticancer therapy and associated with metastasis and relapse in cancer. Although various TIC markers and their antibodies have been proposed, it is limited to the use of antibodies for in vivo imaging or treatment of TIC. In this study, we discovered heme oxygenase 2 (HMOX2) as a novel biomarker for TIC and developed a selective small molecule probe TiNIR (tumor initiating cell probe with near infrared). TiNIR detects and enriches the functionally active TIC in human lung tumors, and through the photoacoustic property, TiNIR also visualizes lung TIC in the patient-derived xenograft (PDX) model. Furthermore, we demonstrate that TiNIR inhibits tumor growth by blocking the function of HMOX2, resulting in significantly increased survival rates of the cancer model mice. The novel therapeutic target HMOX2 and its fluorescent ligand TiNIR will open a new path for the molecular level of lung TIC diagnosis and treatment.
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- 2019
31. Degradation behaviors of naproxen by a hybrid TiO
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Sang-Chul, Jung, Hye-Jin, Bang, Heon, Lee, Hangun, Kim, Hyung-Ho, Ha, Young Hyun, Yu, and Young-Kwon, Park
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Titanium ,Naproxen ,Hydrogen Peroxide ,Microwaves ,Catalysis - Abstract
A hybrid system combining microwave and a microwave discharge electrodeless lamp (MDEL) was proposed to overcome the limitations of conventional TiO
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- 2019
32. Tumidulin, a Lichen Secondary Metabolite, Decreases the Stemness Potential of Colorectal Cancer Cells
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İsa Taş, Suresh R Bhosle, Iris Pereira, Kyung Keun Kim, Chathurika D.B. Gamage, Rui Zhou, Young Hyun Yu, Hangun Kim, Hyung-Ho Ha, So-Yeon Park, Yi Yang, and Jae-Seoun Hur
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0301 basic medicine ,Lichens ,Cell ,Pharmaceutical Science ,stemness potential ,lichen ,Article ,Analytical Chemistry ,lcsh:QD241-441 ,03 medical and health sciences ,0302 clinical medicine ,lcsh:Organic chemistry ,GLI1 ,oncogene ,GLI2 ,Cell Line, Tumor ,Drug Discovery ,medicine ,Tumor Cells, Cultured ,Humans ,transcriptional regulation ,Physical and Theoretical Chemistry ,colorectal cancer cells ,biology ,Oncogene ,Molecular Structure ,Chemistry ,Plant Extracts ,secondary metabolites ,Organic Chemistry ,CD44 ,LGR5 ,Cancer ,medicine.disease ,Molecular biology ,Antineoplastic Agents, Phytogenic ,Gene Expression Regulation, Neoplastic ,tumidulin ,030104 developmental biology ,medicine.anatomical_structure ,Chemistry (miscellaneous) ,030220 oncology & carcinogenesis ,biology.protein ,Neoplastic Stem Cells ,Molecular Medicine ,Smoothened ,Colorectal Neoplasms ,Biomarkers ,Signal Transduction - Abstract
Lichens produce various unique chemicals that are used in the pharmaceutical industry. To screen for novel lichen secondary metabolites that inhibit the stemness potential of colorectal cancer cells, we tested acetone extracts of 11 lichen samples collected in Chile. Tumidulin, isolated from Niebla sp., reduced spheroid formation in CSC221, DLD1, and HT29 cells. In addition, mRNA expressions and protein levels of cancer stem markers aldehyde dehydrogenase-1 (ALDH1), cluster of differentiation 133 (CD133), CD44, Lgr5, and Musashi-1 were reduced after tumidulin treatment. Tumidulin decreased the transcriptional activity of the glioma-associated oncogene homolog zinc finger protein (Gli) promoter in reporter assays, and western blotting confirmed decreased Gli1, Gli2, and Smoothened (SMO) protein levels. Moreover, the tumidulin activity was not observed in the presence of Gli and SMO inhibitors. Together, these results demonstrate for the first time that tumidulin is a potent inhibitor of colorectal cancer cell stemness.
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- 2018
33. Corrigendum to: ‘Physciosporin suppresses the proliferation, motility and tumorigenesis of colorectal cancer cells’ Phytomedicine 56 (2019) 10-20
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Chathurika D.B. Gamage, Jin Han, Kyung-Sub Moon, Tru Van Nguyen, Kyung Keun Kim, Hyung-Ho Ha, İsa Taş, Yi Yang, So-Yeon Park, Jae-Seoun Hur, Hangun Kim, Ji-Yoon Lee, Yong Jae Choi, Sang Kyum Kim, Rui Zhou, and Young Hyun Yu
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Pharmacology ,Physciosporin ,Colorectal cancer ,business.industry ,Pharmaceutical Science ,Motility ,medicine.disease ,medicine.disease_cause ,Phytomedicine ,Complementary and alternative medicine ,Drug Discovery ,medicine ,Cancer research ,Molecular Medicine ,Carcinogenesis ,business - Published
- 2021
34. Degradation behaviors of naproxen by a hybrid TiO2 photocatalyst system with process components
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Hyung-Ho Ha, Hangun Kim, Sang-Chul Jung, Young Hyun Yu, Young-Kwon Park, Hye-Jin Bang, and Heon Lee
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Environmental Engineering ,Materials science ,010504 meteorology & atmospheric sciences ,Radical ,010501 environmental sciences ,01 natural sciences ,Pollution ,law.invention ,Hydroxylation ,chemistry.chemical_compound ,chemistry ,Chemical engineering ,law ,Hybrid system ,Photocatalysis ,Environmental Chemistry ,Degradation (geology) ,Electrodeless lamp ,Hydrogen peroxide ,Waste Management and Disposal ,Microwave ,0105 earth and related environmental sciences - Abstract
A hybrid system combining microwave and a microwave discharge electrodeless lamp (MDEL) was proposed to overcome the limitations of conventional TiO2 photocatalysts. The degradation efficiency and mechanism of naproxen were determined using a series of single processes, including conventional TiO2 photocatalyst reactors and a hybrid system that fuses them. Although the degradation efficiency tended to increase after changing the experimental condition of a single process, the optimal conditions existed for these experimental conditions. On the other hand, remarkable synergy was observed in the fused process, whose efficiency was significantly higher than that of the unit process. In particular, the optimal degradation ability was obtained by adding hydrogen peroxide together with microwave irradiation. The seven intermediates in the proposed photocatalytic degradation pathway were generated by the demethylation and hydroxylation by hydroxyl radicals. These results are expected to provide new data on the design of high efficiency photocatalytic systems at low cost.
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- 2020
35. A heptamethine cyanine dye is a potential diagnostic marker for myeloid-derived suppressor cells
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Yujang Cho, Hyung-Ho Ha, Chaeyong Jung, and Hangun Kim
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biology ,business.industry ,T cell ,Cell ,Cancer ,Hematology ,medicine.disease ,Peripheral blood mononuclear cell ,Arginase ,medicine.anatomical_structure ,Oncology ,Cancer cell ,Myeloid-derived Suppressor Cell ,medicine ,Cancer research ,biology.protein ,Antibody ,business - Abstract
Background Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells with inhibitory effects on T cell proliferation. MDSC are over-amplified in most cancer patients so that cancer cells avoid anticancer immunity. Unlike mouse MDSCs, however, specific surface markers to define human MDSCs is still controversial due its complexity of subsets. Heptamethine cyanine dyes are fluorescent dyes, particularly used for noninvasive in vivo imaging and detection of cancer. MHI-148 is known to be specifically retained by tumor cells but not by normal cells. In this study, we investigated the potential application of MHI-148 as a specific MDSC detection probe. Methods Mice bearing 4T1 breast cancer cells were created in female BALB/c mice. Splenocytes were isolated at 21 days after injection. Cells were stained with anti-Gr-1-FITC, anti-CD11b-PE antibodies for MDSCs or with MHI-148 dye followed by isolating positive cells with cell sorter. To determine whether MHI148-positive cells possess inhibitory effect on T-cell proliferation, EdU-based T cell proliferation assay was performed. Arginase assay and measurement of Nitrite production were also performed for assessing T cell activity inhibition. Results Compared to normal mice, tumor-bearing mice showed tremendous increase of MDSCs (CD11b+/Gr-1+). Over 81% of these MDSCs in tumor bearing mice were reactive to MHI-148 dye. Most sorted cell for MHI-148 fluorescence was also CD11b+/Gr-1+ MDSCs (97.7 %). Notably, lymphocytes and monocytes were not reactive to MHI-148. In addition, MHI-148 dye-positive cells significantly reduced T cell proliferation with increased arginase activity and nitrites concentration, suggesting that MHI-148 reacts to the cells possessing similar function of MDSCs. Conclusions This study demonstrates that MHI-148 reacts to mouse CD11b+/Gr-1+ PBMCs with the function of MDSC characteristics. Further studies have be focused on MHI148 affinity to human MDSC and outcome of which will result in a novel tool to detect MDSC to be utilized to predict cancer patient prognosis. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.
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- 2019
36. Hot mitochondria?
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Howard T. Jacobs, Pierre Rustin, Malgorzata Rak, Riyad El-Khoury, Hyung-Ho Ha, Paule Bénit, Young-Tae Chang, Martin Jastroch, Dominique Chretien, Susanne Keipert, Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), College of Pharmacy [Suncheon, Corée du Sud], Suncheon National University [Suncheon, Corée du Sud], Institute for Diabetes and Obesity [Neuherberg, Allemagne], German Research Center for Environmental Health - Helmholtz Center München (GmbH), Neuromuscular Diagnostic Laboratory [Beyrouth, Liban], Department of Pathology & Laboratory Medicine [Beyrouth, Liban], American University of Beirut Medical Center [Beyrouth, Liban] (AUBMC), American University of Beirut [Beyrouth] (AUB)-American University of Beirut [Beyrouth] (AUB)-American University of Beirut Medical Center [Beyrouth, Liban] (AUBMC), American University of Beirut [Beyrouth] (AUB)-American University of Beirut [Beyrouth] (AUB), Department of Chemistry [Pohang, Corée du Sud], Pohang University of Science and Technology (POSTECH), Institute of Biosciences and Medical Technology [Tampere, Finlande] (BioMediTech), University of Tampere [Finland], Tampere University Hospital, HiLIFE - Institute of Biotechnology [Helsinki] (BI), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Centre National de la Recherche Scientifique (CNRS), European Research Council (grant number 232738). Received by HTJ. Academy Professorship (grant number 256615). Received by HTJ. Academy of Finland (grant number FinMIT CoE 272376). Received by HTJ. Ouvrir Les Yeux (OLY). Received by PB and PR. Association Française contre l'Ataxie de Friedreich (AFAF). Received by PB and PR. Association contre les Maladies Mitochondriales (AMMi). Received by DC, PB, MR, and PR. Association d'Aide aux Jeunes Infirmes (AAJI). Received by PB and PR. E-Rare (grant number E-rare Genomit). Received by DC, PB, MR, and PR. ANR (grant number ANR MITOXDRUGS-DS0403). Received by DC, PB, MR, and PR. ANR (grant number ANR FIFA2-12-BSV1-0010). Received by DC, PB, MR, and PR., ANR-12-BSV1-0010,FiFA2,Combattre l'Ataxie de Friedreich: utilisation de modèles biologiques complémentaires pour le criblage et l'optimisation de nouvelles molécules thérapeutiques(2012), European Project: 232738,EC:FP7:ERC,ERC-2008-AdG,MITO BY-PASS(2009), University of Helsinki-University of Helsinki, Bodescot, Myriam, BLANC - Combattre l'Ataxie de Friedreich: utilisation de modèles biologiques complémentaires pour le criblage et l'optimisation de nouvelles molécules thérapeutiques - - FiFA22012 - ANR-12-BSV1-0010 - BLANC - VALID, and Molecular by-pass therapy for mitochondrial dysfunction - MITO BY-PASS - - EC:FP7:ERC2009-04-01 - 2015-03-31 - 232738 - VALID
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Hot Temperature ,Luminescence ,Physiology ,Respiratory chain ,Mitochondrion ,Toxicology ,Pathology and Laboratory Medicine ,Biochemistry ,0302 clinical medicine ,Cytosol ,Short Reports ,Animal Cells ,Medicine and Health Sciences ,Uncoupling protein ,Biology (General) ,Uncoupling Protein 1 ,Energy-Producing Organelles ,Plant Proteins ,Skin ,Connective Tissue Cells ,chemistry.chemical_classification ,0303 health sciences ,ATP synthase ,biology ,Physics ,Electromagnetic Radiation ,Temperature ,Thermogenesis ,Mitochondria ,Electrophysiology ,Chemistry ,Connective Tissue ,Mitochondrial Membranes ,Physical Sciences ,Cellular Structures and Organelles ,Anatomy ,Cellular Types ,Oxidoreductases ,Chemical Elements ,Alternative oxidase ,QH301-705.5 ,Primary Cell Culture ,Toxic Agents ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Bioenergetics ,Membrane Potential ,Fluorescence ,Mitochondrial Proteins ,03 medical and health sciences ,Humans ,[SDV.BC] Life Sciences [q-bio]/Cellular Biology ,030304 developmental biology ,Fluorescent Dyes ,Cyanides ,HEK 293 cells ,Chemical Compounds ,Biology and Life Sciences ,Kidneys ,Metabolism ,Cell Biology ,Renal System ,Fibroblasts ,Oxygen ,Enzyme ,HEK293 Cells ,Biological Tissue ,chemistry ,biology.protein ,Biophysics ,Salts ,030217 neurology & neurosurgery - Abstract
In endothermic species, heat released as a product of metabolism ensures stable internal temperature throughout the organism, despite varying environmental conditions. Mitochondria are major actors in this thermogenic process. Part of the energy released by the oxidation of respiratory substrates drives ATP synthesis and metabolite transport, but a substantial proportion is released as heat. Using a temperature-sensitive fluorescent probe targeted to mitochondria, we measured mitochondrial temperature in situ under different physiological conditions. At a constant external temperature of 38 °C, mitochondria were more than 10 °C warmer when the respiratory chain (RC) was fully functional, both in human embryonic kidney (HEK) 293 cells and primary skin fibroblasts. This differential was abolished in cells depleted of mitochondrial DNA or treated with respiratory inhibitors but preserved or enhanced by expressing thermogenic enzymes, such as the alternative oxidase or the uncoupling protein 1. The activity of various RC enzymes was maximal at or slightly above 50 °C. In view of their potential consequences, these observations need to be further validated and explored by independent methods. Our study prompts a critical re-examination of the literature on mitochondria., Author summary To ensure a stable internal temperature, endothermic species make use of the heat released during the final steps of food burning by the mitochondria present in all cells of the organism. Indeed, only a fraction of the energy released by the oxidation of respiratory substrates is used to generate ATP, while a substantial proportion is released as heat. Using a temperature-sensitive fluorescent probe targeted to mitochondria, we measured the temperature of active mitochondria in cultured intact human cells. Mitochondria were found to be more than 10 °C warmer when the respiratory chain was functional. This differential was abolished in cells depleted of mitochondrial DNA or by respiratory inhibitors but preserved or enhanced by the expression of thermogenic enzymes such as Ciona alternative oxidase or by uncoupling protein 1. The activity of various respiratory chain enzymes was found to be maximal near 50 °C. Note that in view of their potential consequences, the observations reported here need to be validated and explored further by independent methods.
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- 2018
37. Diversity-Oriented Approach for Chemical Biology
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Nam-Young Kang, Hyung-Ho Ha, Young-Tae Chang, Jun-Seok Lee, and Jae Wook Lee
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Research groups ,Combinatorial Chemistry Techniques ,Computer science ,General Chemical Engineering ,media_common.quotation_subject ,Chemical biology ,Small Molecule Libraries ,Nanotechnology ,General Chemistry ,respiratory system ,Biochemistry ,Field (computer science) ,Materials Chemistry ,Identification (biology) ,Biochemical engineering ,Target protein ,human activities ,Diversity (politics) ,media_common - Abstract
Synthetic molecules that modulate and probe biological events are critical tools in chemical biology. Utilizing combinatorial and diversity-oriented synthetic strategies, access to large numbers of small molecules is becoming more and more feasible, and research groups in this field can take advantage of the power of chemical diversity. Since the majority of early studies were focused on the discovery of compounds that perturb protein functions, diversity-based approaches are often considered as therapeutic lead discovery tactics. However, the diversity-oriented approach can also be applied to advance distinct aims, such as target protein identification, or the development of imaging probes and sensors. This review provides a personal perspective of the chemical-diversity-based approach and how this principle can be adapted to various chemical biology studies.
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- 2015
38. Chemical Targeting of GAPDH Moonlighting Function in Cancer Cells Reveals Its Role in Tubulin Regulation
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Hyung-Ho Ha, Da-Woon Jung, Shinae Seo, Darren R. Williams, Young-Tae Chang, Soon-Ho Yim, Woong-Hee Kim, and Eun-Sang Oh
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Cytoplasm ,Cell Survival ,Alpha-enolase ,Clinical Biochemistry ,Down-Regulation ,Antineoplastic Agents ,Biochemistry ,stomatognathic system ,Cell Movement ,Tubulin ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Animals ,Humans ,RNA, Messenger ,Enzyme Inhibitors ,Molecular Biology ,Zebrafish ,Glyceraldehyde 3-phosphate dehydrogenase ,chemistry.chemical_classification ,Pharmacology ,biology ,Triazines ,Drug discovery ,Glyceraldehyde-3-Phosphate Dehydrogenases ,Cell migration ,General Medicine ,HCT116 Cells ,Cell biology ,Actin Cytoskeleton ,Enzyme ,chemistry ,Enzyme inhibitor ,Larva ,Cancer cell ,biology.protein ,Molecular Medicine ,HT29 Cells - Abstract
Summary Glycolytic enzymes are attractive anticancer targets. They also carry out numerous, nonglycolytic "moonlighting" functions in cells. In this study, we investigated the anticancer activity of the triazine small molecule, GAPDS, that targets the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). GAPDS showed greater toxicity against cancer cells compared to a known GAPDH enzyme inhibitor. GAPDS also selectively inhibited cell migration and invasion. Our analysis showed that GAPDS treatment reduced GAPDH levels in the cytoplasm, which would modulate the secondary, moonlighting functions of this enzyme. We then used GAPDS as a probe to demonstrate that a moonlighting function of GAPDH is tubulin regulation, which may explain its anti-invasive properties. We also observed that GAPDS has potent anticancer activity in vivo. Our study indicates that strategies to target the secondary functions of anticancer candidates may yield potent therapeutics and useful chemical probes.
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- 2014
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39. ENOblock, a unique small molecule inhibitor of the non-glycolyticfunctions of enolase, alleviates the symptoms of type 2 diabetes
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Youngkeun Ahn, Wan Seok Kang, Yong-Chul Kim, JungIn Um, Da-Woon Jung, Woong-Hee Kim, Hyung-Ho Ha, Darren R. Williams, Ji-Hyung Lee, So Hun Kim, and Haaglim Cho
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0301 basic medicine ,Male ,endocrine system diseases ,Enolase ,Active Transport, Cell Nucleus ,Pharmacology ,Article ,Diabetes Mellitus, Experimental ,03 medical and health sciences ,Mice ,Fibrosis ,Diabetes mellitus ,Medicine ,Animals ,Glycolysis ,Cell Nucleus ,Multidisciplinary ,business.industry ,Triazines ,medicine.disease ,030104 developmental biology ,Biochemistry ,Diabetes Mellitus, Type 2 ,Apoptosis ,Phosphopyruvate Hydratase ,Benzamides ,NIH 3T3 Cells ,Experimental pathology ,business ,Rosiglitazone ,Phosphoenolpyruvate carboxykinase ,medicine.drug - Abstract
Type 2 diabetes mellitus (T2DM) significantly impacts on human health and patient numbers are predicted to rise. Discovering novel drugs and targets for treating T2DM is a research priority. In this study, we investigated targeting of the glycolysis enzyme, enolase, using the small molecule ENOblock, which binds enolase and modulates its non-glycolytic ‘moonlighting’ functions. In insulin-responsive cells ENOblock induced enolase nuclear translocation, where this enzyme acts as a transcriptional repressor. In a mammalian model of T2DM, ENOblock treatment reduced hyperglycemia and hyperlipidemia. Liver and kidney tissue of ENOblock-treated mice showed down-regulation of known enolase target genes and reduced enolase enzyme activity. Indicators of secondary diabetic complications, such as tissue apoptosis, inflammatory markers and fibrosis were inhibited by ENOblock treatment. Compared to the well-characterized anti-diabetes drug, rosiglitazone, ENOblock produced greater beneficial effects on lipid homeostasis, fibrosis, inflammatory markers, nephrotoxicity and cardiac hypertrophy. ENOblock treatment was associated with the down-regulation of phosphoenolpyruvate carboxykinase and sterol regulatory element-binding protein-1, which are known to produce anti-diabetic effects. In summary, these findings indicate that ENOblock has potential for therapeutic development to treat T2DM. Previously considered as a ‘boring’ housekeeping gene, these results also implicate enolase as a novel drug target for T2DM.
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- 2017
40. Abstract 2011: Potassium usnate inhibits invasion and metastasis in colorectal cancer: Implication of clinical application of a water-soluble form of usnic acid in anticancer therapy
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Kyung-Hwa Lee, Sueun Lee, Woo Kyun Bae, İsa Taş, Hyung-Ho Ha, Kyung Keun Kim, So-Yeon Park, Rui Zhou, Chathurika D.B. Gamage, Kyung-Sub Moon, Chaeyong Jung, Yi Yang, and Hangun Kim
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Cancer Research ,Colorectal cancer ,Usnic acid ,Cancer ,medicine.disease ,In vitro ,Bioavailability ,Metastasis ,chemistry.chemical_compound ,Oncology ,chemistry ,In vivo ,Oral administration ,medicine ,Cancer research - Abstract
Usnic acid (UA), a lichen secondary substance, has considerable anticancer activity in vitro, whereas its effect in vivo is limited. Here, potassium usnate (KU) was prepared by the salinization of UA to enhance its water solubility. KU showed increased bioavailability compared with UA in the tumor, liver, and plasma of a CT26 syngeneic mouse tumor xenograft model after oral administration, as determined by LC-MS/MS analysis. KU exhibited potent anticancer effects on colorectal cancer cells and inhibited liver metastasis in an orthotopic murine colorectal cancer model. KU treatment downregulated the epithelial-mesenchymal markers Twist, Snail, and Slug and the metastasis-related genes CAPN1, CDC42, CFL1, IGF1, WASF1, and WASL in cells and tumor tissues. The present results suggest the potential application of the water-soluble form of UA, KU, in anticancer therapy. Citation Format: Yi Yang, Woo Kyun Bae, Kyung Hwa Lee, Kyung-Sub Moon, So-Yeon Park, Rui Zhou, Isa Taş, Chathurika Gamage, Sueun Lee, Chaeyong Jung, Kyung Keun Kim, Hyung-Ho Ha, Hangun Kim. Potassium usnate inhibits invasion and metastasis in colorectal cancer: Implication of clinical application of a water-soluble form of usnic acid in anticancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2011.
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- 2019
41. Visualization and Isolation of Langerhans Islets by a Fluorescent Probe PiY
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Sungjin Park, Nam-Young Kang, Hyung-Ho Ha, George K. Radda, Weiping Han, Seong-Wook Yun, Yogeswari Chandran, Hang-Suk Chun, Natalia Gustavsson, Elena Kostromina, Young-Tae Chang, Yusuf Ali, Jin Hee Ahn, Myung Ae Bae, and Sung-Chan Lee
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Population ,Nanotechnology ,Cell Separation ,Glucagon ,Catalysis ,Alpha cell ,Diabetes Mellitus, Experimental ,Islets of Langerhans ,Mice ,Ion binding ,medicine ,Animals ,education ,Cells, Cultured ,Fluorescent Dyes ,education.field_of_study ,Molecular Structure ,Chemistry ,Pancreatic islets ,General Medicine ,General Chemistry ,Molecular biology ,Disease Models, Animal ,medicine.anatomical_structure ,Microscopy, Fluorescence ,Stem cell ,Pancreas ,Immunostaining - Abstract
Pancreatic Langerhans islets are mainly composed of insulinsecreting beta cells and glucagon-secreting alpha cells, along with other minor cell types, and play a central role in the regulation of blood glucose levels. Because of this, imaging of viable pancreatic islets is an important component in research on diabetes both in clinical and experimental medicine. The conventional imaging technique for pancreatic islets is antibody-based immunostaining directly on pancreatic sections, or using transgenic mice with luminescent reporter genes linked to islet-specific promoters. Among small molecule probes, Newport Green and dithiazone (DTZ) have been used for ex vivo fluorescent staining of pancreatic islets, based on their Zn ion binding affinity, which are abundant in beta cells in complex with insulin. For in situ application, fluorescently labeled exendin-4 (a GLP1R binding peptide: M.W. is about 5 kDa) has been recently introduced for the measurement of the mass of pancreatic islet beta cells. However, small molecule probes for selective staining of beta cells in pancreatic islets of live animals have not yet been reported. We predicted that a diversity-oriented fluorescence library approach (DOFLA), an expedited bioimaging probe discovery method using high throughput synthesis and high contents screening, would be a powerful method to achieve this goal. Using a similar approach, we have previously elucidated probes for pluripotent stem cells (CDy1), muscle cells (CDy2), neuronal stem cells (CDr3), and pancreatic alpha cells (GY= glucagon yellow). Although the glucagon-targeting probe GY selectively stains alpha cells in isolated cell culture, it did not clearly mark mouse pancreatic islets in tissue, partially owing to the small population of alpha cells (around 15–20% in mouse islets). We expected that a fluorescent probe for pancreatic beta cells (with a larger population of 75–80% in mouse islets) would be more effective for visualizing pancreatic islets. As a first step, we synthesized fluorescent smallmolecule libraries composed of 1200 compounds, and screened them against beta TC-6 cells in comparison to alpha TC-1 cells and acinar cells (exocrine cells in the pancreas) as controls. The three cell types were compared in 384-well plates and incubated with the library compounds (1 mm) at incubation times ranging from one to 48 hours. The fluorescence live-cell images were acquired by an automated imaging microscope system, ImageXpress Micro. One compound from the BDNCA series (Scheme 1), BDNCA-325 (labs/lem= 558/585 nm, extinction cooefficient e= 58,000m 1 cm , quantum yield F= 0.06) was chosen as the most selective for the beta TC-6 cells (Figure 1a) in comparison to the two control cell types in terms of relative fluorescence intensity. The BDNCA library was prepared from a BODIPY-aniline (BDN) series by chloroacetylation. While BDN has very low fluorescence emission (less than 1% quantum yield) owing to photoinduced electron transfer (PET), by converting the amine to an amide, the fluorescence of BDNCA was moderately increased (F= 5–10%). Therefore, this amide motif is a modulator of the fluorescence intensity of the BDNCA series through interaction with the surrounding environment or binding partner. However, when we injected BDNCA-325 intravenously into a mouse, the pancreatic islets were not selectively stained at various incubation times and concentrations (data not shown). Because BDNCA-325 contains a chemically reactive chloroacetyl group, we hypothesized that the compound might have reacted with other tissues in the animal before reaching the pancreatic islets. Thus, BDNCA-325 was modified by removing the reactive alpha-chloride and also by [*] Dr. N.-Y. Kang, Dr. S.-C. Lee, Dr. S.-J. Park, Dr. S.-W. Yun, Dr. E. Kostromina, Dr. N. Gustavsson, Dr. Y. Ali, Y. Chandran, Dr. W. Han, Dr. G. K. Radda, Prof. Y.-T. Chang Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR) 138667, Singapore (Singapore) E-mail: chmcyt@nus.edu.sg Homepage: http://ytchang.science.nus.edu.sg
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- 2013
42. A Unique Small Molecule Inhibitor of Enolase Clarifies Its Role in Fundamental Biological Processes
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Hyung-Ho Ha, Dongdong Su, Woong-Hee Kim, Jinho Lee, Jinmi Kim, Da-Woon Jung, Darren R. Williams, Young-Tae Chang, and Si-Hwan Park
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Protein moonlighting ,Alpha-enolase ,Molecular Sequence Data ,Enolase ,Antineoplastic Agents ,Biochemistry ,Small Molecule Libraries ,Cell Movement ,In vivo ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Animals ,Humans ,Glucose homeostasis ,Neoplasm Invasiveness ,Amino Acid Sequence ,Enzyme Inhibitors ,Zebrafish ,Adipogenesis ,biology ,Triazines ,Drug discovery ,General Medicine ,Small molecule ,Cell biology ,Glucose ,Phosphopyruvate Hydratase ,Benzamides ,Cancer cell ,biology.protein ,Molecular Medicine ,Foam Cells - Abstract
Enolase is a component of the glycolysis pathway and a "moonlighting" protein, with important roles in diverse cellular processes that are not related to its function in glycolysis. However, small molecule tools to probe enolase function have been restricted to crystallography or enzymology. In this study, we report the discovery of the small molecule "ENOblock", which is the first, nonsubstrate analogue that directly binds to enolase and inhibits its activity. ENOblock was isolated by small molecule screening in a cancer cell assay to detect cytotoxic agents that function in hypoxic conditions, which has previously been shown to induce drug resistance. Further analysis revealed that ENOblock can inhibit cancer cell metastasis in vivo. Moreover, an unexpected role for enolase in glucose homeostasis was revealed by in vivo analysis. Thus, ENOblock is the first reported enolase inhibitor that is suitable for biological assays. This new chemical tool may also be suitable for further study as a cancer and diabetes drug candidate.
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- 2013
43. A fluorescent screening platform for the rapid evaluation of chemicals in cellular reprogramming
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Chi-Lik Ken Lee, Yogeswari Chandran, Young-Tae Chang, Sungjin Park, Nam-Young Kang, Seong-Wook Yun, Marc Vendrell, and Hyung-Ho Ha
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Morpholines ,Cellular differentiation ,Induced Pluripotent Stem Cells ,Mice, SCID ,Biology ,Mice ,Transduction (genetics) ,SOX2 ,High-Throughput Screening Assays ,Animals ,Induced pluripotent stem cell ,Cells, Cultured ,Fluorescent Dyes ,Medicine(all) ,Anthracenes ,Drug discovery ,SOXB1 Transcription Factors ,Cell Differentiation ,Cell Biology ,General Medicine ,Fibroblasts ,Molecular biology ,Cell biology ,Microscopy, Fluorescence ,Histone deacetylase ,Octamer Transcription Factor-3 ,Reprogramming ,Developmental Biology - Abstract
Current strategies to monitor reprogramming into induced pluripotent stem cells (iPSCs) are limited in that they rely on the recognition of advanced stage biomarkers or they involve the transduction of genetically-modified cells. These limitations are particularly problematic in high-throughput screenings where cell availability, low cost and a rapid experimental protocol are critical issues. Herein we report the application of a pluripotent stem cell fluorescent probe (i.e. CDy1) as a reporter for the rapid screening of chemicals in reprogramming iPSCs. CDy1 stains early-stage iPSCs at 7dpi as well as matured iPSCs; hence it can partially overcome the slow kinetics of the reprogramming process. As a proof of concept, we employed a CDy1-based screening in 384 well-plates to examine the effect of newly synthesized hydroxamic acid derivatives in reprogramming mouse fibroblasts transduced with Oct4, Sox2 and Klf-4 without c-Myc. One compound (1–26) was identified as a reprogramming enhancer by 2.5-fold and we confirmed that 1–26 behaves as a histone deacetylase (HDAC) inhibitor. The successful identification of novel small molecules enhancing the generation of iPSCs by means of a rapid and simple protocol demonstrates the suitability of this CDy1-based screening platform for the large scale and high-throughput evaluation of iPSC modulators.
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- 2012
44. Control of muscle differentiation by a mitochondria-targeted fluorophore
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Yun Kyung Kim, Hyung-Ho Ha, Jun-Seok Lee, Xuezhi Bi, Young-Hoon Ahn, Hajar, Siti, Jae-Jung Lee, and Young-Tae Chang
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Muscle proteins -- Chemical properties ,Myogenesis -- Analysis ,Biosensors -- Research ,Fluorescence -- Analysis ,Mitochondria -- Physiological aspects ,Chemistry - Abstract
A mitochondria-targeted rosamine library in C2C12 myogenesis was applied to identify the compound that regulates the muscle differentiation during the remarkable changes undergone by mitochondria. The findings from the study provide insight into the potential application of fluorescent small molecules in the discovery of a bioactive probe that induces a specific cellular response.
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- 2010
45. Development of background-free tame fluorescent probes for intracellular live cell imaging
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Lingna Hu, Enrique Alvarado-Martínez, Young-Tae Chang, Hee-Sung Park, Rudrakanta Satapathy, Christian Hoppmann, Jihyo Kim, Eduardo Peña-Cabrera, Lei Wang, Haiyan Ren, Samira Husen Alamudi, Dongdong Su, Raj Kumar Das, Jung Yeol Lee, and Hyung-Ho Ha
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Gene Expression ,Golgi Apparatus ,General Physics and Astronomy ,Signal-To-Noise Ratio ,01 natural sciences ,Cyclooctanes ,chemistry.chemical_compound ,chemistry.chemical_classification ,Tumor ,Multidisciplinary ,Fluorescence ,Recombinant Proteins ,Mitochondria ,Molecular Imaging ,3. Good health ,Cell biology ,Cheminformatics ,BODIPY ,Cell Nucleolus ,Intracellular ,Biotechnology ,Boron Compounds ,Azides ,Science ,Bioengineering ,CHO Cells ,Biology ,010402 general chemistry ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Cricetulus ,Live cell imaging ,Cell Line, Tumor ,Animals ,Humans ,Fluorescent Dyes ,Osteoblasts ,Staining and Labeling ,010405 organic chemistry ,Biomolecule ,Rational design ,General Chemistry ,High-Throughput Screening Assays ,0104 chemical sciences ,chemistry ,Drug Design ,Molecular imaging ,Lysosomes - Abstract
Fluorescence labelling of an intracellular biomolecule in native living cells is a powerful strategy to achieve in-depth understanding of the biomolecule's roles and functions. Besides being nontoxic and specific, desirable labelling probes should be highly cell permeable without nonspecific interactions with other cellular components to warrant high signal-to-noise ratio. While it is critical, rational design for such probes is tricky. Here we report the first predictive model for cell permeable background-free probe development through optimized lipophilicity, water solubility and charged van der Waals surface area. The model was developed by utilizing high-throughput screening in combination with cheminformatics. We demonstrate its reliability by developing CO-1 and AzG-1, a cyclooctyne- and azide-containing BODIPY probe, respectively, which specifically label intracellular target organelles and engineered proteins with minimum background. The results provide an efficient strategy for development of background-free probes, referred to as ‘tame' probes, and novel tools for live cell intracellular imaging., The success of a fluorescent dye as a molecular probe to monitor the intracellular activity of biomolecules depends on its physicochemical characteristics. Here, the authors use a predictive model to identify key features that allow them to design cell permeable, background-free fluorescent probes.
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- 2016
46. Combinatorial Solid-Phase Synthesis of 4,6-Diaryl and 4-Aryl, 6-Alkyl-1,3,5-triazines and Their Application to Efficient Biofuel Production
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Youngsook Lee, Hyung-Ho Ha, Marc Vendrell, Woo Sirl Lee, Jaoon Y.H. Kim, Young-Tae Chang, Jae Wook Lee, and Jacqueline T. Bork
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chemistry.chemical_classification ,Triazines ,Aryl ,Grignard reaction ,General Chemistry ,General Medicine ,Biolipid ,Combinatorial chemistry ,Small Molecule Libraries ,chemistry.chemical_compound ,Solid-phase synthesis ,Suzuki reaction ,chemistry ,Biofuel ,Biofuels ,Combinatorial Chemistry Techniques ,Organic chemistry ,Solid-Phase Synthesis Techniques ,Alkyl ,Triazine - Abstract
Herein we report the solid-phase synthesis of a combinatorial aryl, alkyl-triazine library and its application to biofuel production. The combination of Grignard reactions and solid supported Suzuki coupling reactions afforded unique 120 triazine compounds with high purities and minimum purification steps. Through an unbiased phenotypic screening for improved biofuel generation in oleaginous yeast, we found one diaryl triazine derivative (E4) which increased the biolipid production up to 86%.
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- 2012
47. Embryonic and induced pluripotent stem cell staining and sorting with the live-cell fluorescence imaging probe CDy1
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Hyung-Ho Ha, Sungjin Park, Nam-Young Kang, Seong-Wook Yun, and Young-Tae Chang
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Anthracenes ,Staining and Labeling ,Morpholines ,Regeneration (biology) ,Induced Pluripotent Stem Cells ,Cell Culture Techniques ,Cell sorting ,Biology ,Flow Cytometry ,Cell morphology ,Molecular biology ,Embryonic stem cell ,General Biochemistry, Genetics and Molecular Biology ,Cell biology ,Cell culture ,Stem cell ,Induced pluripotent stem cell ,Embryonic Stem Cells ,Immunostaining ,Fluorescent Dyes - Abstract
Detecting and isolating specific types of cells is crucial to understanding a variety of biological processes, including development, aging, regeneration and pathogenesis; this understanding, in turn, allows the use of cells for therapeutic purposes, for which stem cells have emerged recently as invaluable materials. The current methods of isolation and characterization of stem cells depend on cell morphology in culture or on immunostaining of specific markers. These methods are, however, time consuming and involve the use of antibodies that may often make the cells unsuitable for further study. We recently developed a fluorescent small molecule named CDy1 (compound of designation yellow 1) that selectively stains live embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). This protocol describes detailed procedures for staining ESC and iPSC in live conditions and for fluorescence-activated cell sorting (FACS) of ESC using CDy1. Cell staining, image acquisition and FACS can be done within 6 h.
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- 2011
48. Glycoprotein 90K Promotes E-Cadherin Degradation in a Cell Density-Dependent Manner via Dissociation of E-Cadherin–p120-Catenin Complex
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Hyung-Ho Ha, Jung-Il Chae, Somy Yoon, So-Yeon Park, Man-Jeong Paik, Jeong A Bae, Eun Gene Sun, Kyung Keun Kim, Young-Woo Seo, Rui Zhou, and Hangun Kim
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Male ,0301 basic medicine ,Delta Catenin ,Cell Count ,adherens junction ,Metastasis ,lcsh:Chemistry ,0302 clinical medicine ,Neoplasms ,LGALS3BP ,Mac-2BP ,Phosphorylation ,lcsh:QH301-705.5 ,Spectroscopy ,chemistry.chemical_classification ,Catenins ,General Medicine ,Cadherins ,Prognosis ,90K glycoprotein ,E-cadherin ,p120-catenin ,Computer Science Applications ,Cell biology ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,MCF-7 Cells ,Female ,Down-Regulation ,Motility ,Article ,Catalysis ,Inorganic Chemistry ,Adherens junction ,03 medical and health sciences ,Downregulation and upregulation ,Antigens, CD ,Antigens, Neoplasm ,Cell Line, Tumor ,Biomarkers, Tumor ,Cell Adhesion ,medicine ,Humans ,Neoplasm Invasiveness ,Physical and Theoretical Chemistry ,Molecular Biology ,Glycoproteins ,Cadherin ,Cell Membrane ,Organic Chemistry ,medicine.disease ,HEK293 Cells ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,Proteolysis ,Cancer cell ,Caco-2 Cells ,Carrier Proteins ,Glycoprotein - Abstract
Glycoprotein 90K (also known as LGALS3BP or Mac-2BP) is a tumor-associated protein, and high 90K levels are associated with poor prognosis in some cancers. To clarify the role of 90K as an indicator for poor prognosis and metastasis in epithelial cancers, the present study investigated the effect of 90K on an adherens junctional protein, E-cadherin, which is frequently absent or downregulated in human epithelial cancers. Treatment of certain cancer cells with 90K significantly reduced E-cadherin levels in a cell-population-dependent manner, and these cells showed decreases in cell adhesion and increases in invasive cell motility. Mechanistically, 90K-induced E-cadherin downregulation occurred via ubiquitination-mediated proteasomal degradation. 90K interacted with the E-cadherin–p120-catenin complex and induced its dissociation, altering the phosphorylation status of p120-catenin, whereas it did not associate with β-catenin. In subconfluent cells, 90K decreased membrane-localized p120-catenin and the membrane fraction of the p120-catenin. Particularly, 90K-induced E-cadherin downregulation was diminished in p120-catenin knocked-down cells. Taken together, 90K upregulation promotes the dissociation of the E-cadherin–p120-catenin complex, leading to E-cadherin proteasomal degradation, and thereby destabilizing adherens junctions in less confluent tumor cells. Our results provide a potential mechanism to explain the poor prognosis of cancer patients with high serum 90K levels.
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- 2017
49. Inhibition of H2O2-induced neuroblastoma cell cytotoxicity by a triazine derivative, AA3E2
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Hyung-Ho Ha, Hamed Shaykhalishahi, Razieh Yazdanparast, and Young-Tae Chang
- Subjects
Antioxidant ,Cell Survival ,medicine.medical_treatment ,Pharmacology ,medicine.disease_cause ,Antioxidants ,Superoxide dismutase ,Neuroblastoma ,chemistry.chemical_compound ,Lactate dehydrogenase ,medicine ,Humans ,Mode of action ,Cytotoxicity ,biology ,Superoxide Dismutase ,Triazines ,Hydrogen Peroxide ,Catalase ,Caspase Inhibitors ,chemistry ,Biochemistry ,biology.protein ,Reactive Oxygen Species ,Intracellular ,Oxidative stress - Abstract
Alzheimer's disease is the major cause of senile dementia with the hallmark of beta-amyloid deposition in neurons. Although the main cause(s) of this deposition is not fully understood, however, the wealth of the present literature data supports the pivotal role of reactive oxygen and nitrogen species in both the initiation and progression of beta-amyloid aggregation and deposition. In the present study, we were interested to evaluate the free-radical protecting effect of AA3E2, a triazine derivative with a beta-amyloid-breaking activity, among SK-N-MC neuroblastoma cells exposed to hydrogen peroxide (H(2)O(2)) as an exogenous source of free radicals. Exposure of the cells to different doses of AA3E2 (1-16 microM) for 3h followed by subsequent exposure to a single dose of H(2)O(2) (mainly 150 microM) attenuated the extent of superoxide dismutase (SOD) and catalase (CAT) inhibition by H(2)O(2), in a dose dependent manner. Furthermore, significant reduction was observed in the extent of cellular lactate dehydrogenase release, intracellular ROS and the extent of apoptosis among the cells pre-treated with AA3E2. Based on these data, an antioxidant mode of action is proposed for AA3E2 besides its previously beta-amyloid-breaking activity.
- Published
- 2009
50. Discovery of amyloid-beta aggregation inhibitors using an engineered assay for intracellular protein folding and solubility
- Author
-
Hyung-Ho Ha, Li Ling Lee, Matthew P. DeLisa, and Young-Tae Chang
- Subjects
Models, Molecular ,Protein Folding ,Proteases ,Amyloid beta ,Chemistry, Pharmaceutical ,Recombinant Fusion Proteins ,Drug Evaluation, Preclinical ,Chemical biology ,Peptide ,Protein Sorting Signals ,Biochemistry ,beta-Lactamases ,Article ,Small Molecule Libraries ,chemistry.chemical_compound ,Protein structure ,Alzheimer Disease ,mental disorders ,Escherichia coli ,Protein Structure, Quaternary ,Molecular Biology ,Fluorescent Dyes ,chemistry.chemical_classification ,Amyloid beta-Peptides ,biology ,Triazines ,Escherichia coli Proteins ,Membrane Transport Proteins ,Reproducibility of Results ,nervous system diseases ,Microscopy, Fluorescence ,Solubility ,chemistry ,biology.protein ,Thioflavin ,Protein folding ,Chemical chaperone ,Protein Binding - Abstract
Genetic and biochemical studies suggest that Alzheimer's disease (AD) is caused by a series of events initiated by the production and subsequent aggregation of the Alzheimer's amyloid beta peptide (Abeta), the so-called amyloid cascade hypothesis. Thus, a logical approach to treating AD is the development of small molecule inhibitors that either block the proteases that generate Abeta from its precursor (beta- and gamma-secretases) or interrupt and/or reverse Abeta aggregation. To identify potent inhibitors of Abeta aggregation, we have developed a high-throughput screen based on an earlier selection that effectively paired the folding quality control feature of the Escherichia coli Tat protein export system with aggregation of the 42-residue AD pathogenesis effecter Abeta42. Specifically, a tripartite fusion between the Tat-dependent export signal ssTorA, the Abeta42 peptide and the beta-lactamase (Bla) reporter enzyme was found to be export incompetent due to aggregation of the Abeta42 moiety. Here, we reasoned that small, cell-permeable molecules that inhibited Abeta42 aggregation would render the ssTorA-Abeta42-Bla chimera competent for Tat export to the periplasm where Bla is active against beta-lactam antibiotics such as ampicillin. Using a fluorescence-based version of our assay, we screened a library of triazine derivatives and isolated four nontoxic, cell-permeable compounds that promoted efficient Tat-dependent export of ssTorA-Abeta42-Bla. Each of these was subsequently shown to be a bona fide inhibitor of Abeta42 aggregation using a standard thioflavin T fibrillization assay, thereby highlighting the utility of our bacterial assay as a useful screen for antiaggregation factors under physiological conditions.
- Published
- 2009
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