39 results on '"Eun Soo Kwon"'
Search Results
2. DNA methylome analysis reveals epigenetic alteration of complement genes in advanced metabolic dysfunction-associated steatotic liver disease.
- Author
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Magdy, Amal, Hee-Jin Kim, Hanyong Go, Jun Min Lee, Hyun Ahm Sohn, Keeok Haam, Hyo-Jung Jung, Jong-Lyul Park, Taekyeong Yoo, Eun-Soo Kwon, Dong Hyeon Lee, Murim Choi, Keon Wook Kang, Won Kim, and Mirang Kim
- Published
- 2024
- Full Text
- View/download PDF
3. A subset of microRNAs in the Dlk1‐Dio3 cluster regulates age‐associated muscle atrophy by targeting Atrogin‐1
- Author
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Yeo Jin Shin, Eun‐Soo Kwon, Seung‐Min Lee, Seon‐Kyu Kim, Kyung‐Won Min, Jae‐Young Lim, Bora Lee, Jae Sook Kang, Ju Yeon Kwak, Young Hoon Son, Jeong Yi Choi, Yong Ryul Yang, Seokho Kim, Yeon‐Soo Kim, Hak C. Jang, Yousin Suh, Je‐Hyun Yoon, Kwang‐Pyo Lee, and Ki‐Sun Kwon
- Subjects
Dlk1‐Dio3 miRNA cluster ,Muscle aging ,Sarcopenia ,Atrophy ,Cachexia ,Atrogin‐1 ,Diseases of the musculoskeletal system ,RC925-935 ,Human anatomy ,QM1-695 - Abstract
Abstract Background The microRNAs (miRNAs) down‐regulated in aged mouse skeletal muscle were mainly clustered within the delta‐like homologue 1 and the type III iodothyronine deiodinase (Dlk1‐Dio3) genomic region. Although clustered miRNAs are coexpressed and regulate multiple targets in a specific signalling pathway, the function of miRNAs in the Dlk1‐Dio3 cluster in muscle aging is largely unknown. We aimed to ascertain whether these miRNAs play a common role to regulate age‐related muscle atrophy. Methods To examine anti‐atrophic effect of miRNAs, we individually transfected 42 miRNA mimics in fully differentiated myotubes and analysed their diameters. The luciferase reporter assay using target 3′ untranslated region (UTR) and RNA pull‐down assay were employed to ascertain the target predicted by the TargetScan algorithm. To investigate the therapeutic potential of the miRNAs in vivo, we generated adeno‐associated virus (AAV) serotype 9 expressing green fluorescent protein (GFP) (AAV9‐GFP) bearing miR‐376c‐3p and infected it into the tibialis anterior muscle of old mice. We performed morphometric analysis and measured ex vivo isometric force using a force transducer. Human gluteus maximus muscle tissues (ages ranging from 25 to 80 years) were used to investigate expression levels of the conserved miRNAs in the Dlk1‐Dio3 cluster. Results We found that the majority of miRNAs (33 out of 42 tested) in the cluster induced anti‐atrophic phenotypes in fully differentiated myotubes with increasing their diameters. Eighteen of these miRNAs, eight of which are conserved in humans, harboured predicted binding sites in the 3′ UTR of muscle atrophy gene‐1 (Atrogin‐1) encoding a muscle‐specific E3 ligase. Direct interactions were identified between these miRNAs and the 3′ UTR of Atrogin‐1, leading to repression of Atrogin‐1 and thereby induction of eIF3f protein content, in both human and mouse skeletal muscle cells. Intramuscular delivery of AAV9 expressing miR‐376c‐3p, one of the most effective miRNAs in myotube thickening, dramatically ameliorated skeletal muscle atrophy and improved muscle function, including isometric force, twitch force, and fatigue resistance in old mice. Consistent with our findings in mice, the expression of miRNAs in the cluster was significantly down‐regulated in human muscle from individuals > 50 years old. Conclusions Our study suggests that genetic intervention using a muscle‐directed miRNA delivery system has therapeutic efficacy in preventing Atrogin‐1‐mediated muscle atrophy in sarcopenia.
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- 2020
- Full Text
- View/download PDF
4. Epigenetic Activation of Tensin 4 Promotes Gastric Cancer Progression
- Author
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Haejeong Heo, Hee-Jin Kim, Keeok Haam, Hyun Ahm Sohn, Yang-Ji Shin, Hanyong Go, Hyo-Jung Jung, Jong-Hwan Kim, Sang-Il Lee, Kyu-Sang Song, Min-Ju Kim, Haeseung Lee, Eun-Soo Kwon, Seon-Young Kim, Yong Sung Kim, and Mirang Kim
- Subjects
Cell Biology ,General Medicine ,Molecular Biology - Published
- 2023
5. Molecular mechanisms and therapeutic interventions in sarcopenia
- Author
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Sung Sup Park, Eun-Soo Kwon, and Ki-Sun Kwon
- Subjects
Mechanisms ,Therapy ,Skeletal ,Aging ,Sarcopenia ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Sarcopenia is the degenerative loss of muscle mass and function with aging. Recently sarcopenia was recognized as a clinical disease by the International Classification of Disease, 10th revision, Clinical Modification. An imbalance between protein synthesis and degradation causes a gradual loss of muscle mass, resulting in a decline of muscle function as a progress of sarcopenia. Many mechanisms involved in the onset of sarcopenia include age-related factors as well as activity-, disease-, and nutrition-related factors. The stage of sarcopenia reflecting the severity of conditions assists clinical management of sarcopenia. It is important that systemic descriptions of the disease conditions include age, sex, and other environmental risk factors as well as levels of physical function. To develop a new therapeutic intervention needed is the detailed understanding of molecular and cellular mechanisms by which apoptosis, autophagy, atrophy, and hypertrophy occur in the muscle stem cells, myotubes, and/or neuromuscular junction. The new strategy to managing sarcopenia will be signal-modulating small molecules, natural compounds, repurposing of old drugs, and muscle-specific microRNAs.
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- 2017
- Full Text
- View/download PDF
6. Bacteria-derived metabolite, methylglyoxal, modulates the longevity of C. elegans through TORC2/SGK-1/DAF-16 signaling
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Chankyu Park, Mooncheol Park, Sumi Jang, Jin-Hyuck Jeong, Jun-Seok Han, Jeong-Yoon Kim, Seon-Young Kim, Jong-Hwan Kim, Ki-Sun Kwon, Min-Gi Shin, Kwang Lae Hoe, Kwang-Pyo Lee, Bora Lee, Eun-Soo Kwon, Yong Ryoul Yang, Seokho Kim, Jae-Woong Lee, and So-Hyun Park
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media_common.quotation_subject ,Longevity ,Mechanistic Target of Rapamycin Complex 2 ,Protein Serine-Threonine Kinases ,Models, Biological ,Mitochondrial unfolded protein response ,Daf-16 ,Escherichia coli ,Animals ,Caenorhabditis elegans ,Caenorhabditis elegans Proteins ,Transcription factor ,media_common ,Multidisciplinary ,biology ,FOXO Family ,Forkhead Transcription Factors ,Biological Sciences ,biology.organism_classification ,Pyruvaldehyde ,Cell biology ,Gastrointestinal Microbiome ,Phosphorylation ,Signal transduction ,Transcriptome ,Signal Transduction - Abstract
Gut microbes play diverse roles in modulating host fitness, including longevity; however, the molecular mechanisms underlying their mediation of longevity remain poorly understood. We performed genome-wide screens using 3,792 Escherichia coli mutants and identified 44 E. coli mutants that modulated Caenorhabditis elegans longevity. Three of these mutants modulated C. elegans longevity via the bacterial metabolite methylglyoxal (MG). Importantly, we found that low MG-producing E. coli mutants, Δhns E. coli, extended the lifespan of C. elegans through activation of the DAF-16/FOXO family transcription factor and the mitochondrial unfolded protein response (UPR(mt)). Interestingly, the lifespan modulation by Δhns did not require insulin/insulin-like growth factor 1 signaling (IIS) but did require TORC2/SGK-1 signaling. Transcriptome analysis revealed that Δhns E. coli activated novel class 3 DAF-16 target genes that were distinct from those regulated by IIS. Taken together, our data suggest that bacteria-derived MG modulates host longevity through regulation of the host signaling pathways rather than through nonspecific damage on biomolecules known as advanced glycation end products. Finally, we demonstrate that MG enhances the phosphorylation of hSGK1 and accelerates cellular senescence in human dermal fibroblasts, suggesting the conserved role of MG in controlling longevity across species. Together, our studies demonstrate that bacteria-derived MG is a novel therapeutic target for aging and aging-associated pathophysiology.
- Published
- 2020
7. Pancreatic cancer induces muscle wasting by promoting the release of pancreatic adenocarcinoma upregulated factor
- Author
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Eunsung Jun, Eun Soo Kwon, Sang Seok Koh, Yong Ryoul Yang, Yousun Ko, Kyung Hee Noh, Seongyea Jo, Young Hoon Son, Yeon Jeong Kim, Hyunji Choi, Jaemin Lee, Kyung Won Kim, Dana Jung, Kwang-Pyo Lee, Wonbeak Yoo, Seokho Kim, and Song Cheol Kim
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Male ,Cachexia ,Clinical Biochemistry ,Apoptosis ,Adenocarcinoma ,Biochemistry ,Article ,Metastasis ,Mice ,Atrophy ,Weight loss ,Pancreatic cancer ,medicine ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Animals ,Humans ,Molecular Biology ,Wasting ,Cell Proliferation ,business.industry ,Middle Aged ,medicine.disease ,Prognosis ,Xenograft Model Antitumor Assays ,Muscle atrophy ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,Muscular Atrophy ,Cancer research ,Molecular Medicine ,Intercellular Signaling Peptides and Proteins ,Female ,medicine.symptom ,business - Abstract
Cancer cachexia is a highly debilitating condition characterized by weight loss and muscle wasting that contributes significantly to the morbidity and mortality of pancreatic cancer. The factors that induce cachexia in pancreatic cancer are largely unknown. We previously showed that pancreatic adenocarcinoma upregulated factor (PAUF) secreted by pancreatic cancer cells is responsible for tumor growth and metastasis. Here, we analyzed the relation between pancreatic cancer-derived PAUF and cancer cachexia in mice and its clinical significance. Body weight loss and muscle weight loss were significantly higher in mice with Panc-1/PAUF tumors than in those with Panc-1/Mock tumors. Direct administration of rPAUF to muscle recapitulated tumor-induced atrophy, and a PAUF-neutralizing antibody abrogated tumor-induced muscle wasting in Panc-1/PAUF tumor-bearing mice. C2C12 myotubes treated with rPAUF exhibited rapid inactivation of Akt-Foxo3a signaling, resulting in Atrogin1/MAFbx upregulation, myosin heavy chain loss, and muscle atrophy. The neutrophil-to-lymphocyte ratio and body weight loss were significantly higher in pancreatic cancer patients with high PAUF expression than in those with low PAUF expression. Analysis of different pancreatic cancer datasets showed that PAUF expression was significantly higher in the pancreatic cancer group than in the nontumor group. Analysis of The Cancer Genome Atlas data found associations between high PAUF expression or a high DNA copy number and poor overall survival. Our data identified tumor-secreted circulating PAUF as a key factor of cachexia, causing muscle wasting in mice. Neutralizing PAUF may be a useful therapeutic strategy for the treatment of pancreatic cancer-induced cachexia., Pancreatic cancer: Protein promotes cancer-related weight loss A protein involved in tumor growth is also a likely cause of weight loss during pancreatic cancer, and may be a useful target for prognosis and treatment. Pancreatic adenocarcinoma upregulated factor (PAUF) is secreted by pancreatic cancer cells and is also found in other cancers where significant weight loss occurs. Wonbeak Yoo, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea, and co-workers examined the role of PAUF in cancer-related weight loss in mice. Mice inoculated with PAUF-expressing cancer cells experienced weight loss despite no change in food consumption. PAUF increased muscle atrophy and triggered muscle wasting pathways. PAUF is routinely measured in cancer patients, and could therefore provide a convenient biomarker to inform treatment decisions. The researchers suggest that neutralising PAUF could be a valuable therapeutic option.
- Published
- 2020
8. 3′-Sialyllactose as an inhibitor of p65 phosphorylation ameliorates the progression of experimental rheumatoid arthritis
- Author
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Wook Kim, Sang-Rae Lee, Kwang Min Lee, Siyoung Yang, Chanmi Cho, Young Bae Ryu, Eun-Soo Kwon, Jimin Jeon, Mi Ra Cho, Tae Hyun Youm, Seon-Yong Jeong, Li-Jung Kang, and Jae-In Lee
- Subjects
0301 basic medicine ,Pharmacology ,Chemokine ,biology ,business.industry ,Arthritis ,Matrix metalloproteinase ,medicine.disease ,Proinflammatory cytokine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,In vivo ,Rheumatoid arthritis ,Synovitis ,medicine ,biology.protein ,business ,030217 neurology & neurosurgery - Abstract
Background and purpose 3'-Sialyllactose (3'-SL) is a safe compound that is present in high levels in human milk. Although it has anti-inflammatory properties and supports immune homeostasis, its effect on collagen-induced arthritis (CIA) is unknown. In this study, we investigated the prophylactic and therapeutic effect of 3'-SL on the progression of rheumatoid arthritis (RA) in in vitro and in vivo models. Experimental approach The anti-arthritic effect of 3'-SL was analysed with fibroblast-like synoviocytes in vitro and an in vivo mouse model of CIA. RT-PCR, Western blotting and ELISA were performed to evaluate its effects in vitro. Histological analysis of ankle and knee joints of mice with CIA was performed using immunohistochemistry, as well as safranin-O and haematoxylin staining. Key results 3'-SL markedly alleviated the severity of CIA in the mice by reducing paw swelling, clinical scores, incidence rate, serum levels of inflammatory cytokines and autoantibody production. Moreover, 3'-SL reduced synovitis and pannus formation and suppressed cartilage destruction by blocking secretion of chemokines, pro-inflammatory cytokines, matrix metalloproteinases and osteoclastogenesis via NF-κB signalling. Notably, phosphorylation of p65, which is a key protein in the NF-κB signalling pathway, was totally blocked by 3'-SL in the RA models. Conclusions and implications 3'-SL ameliorated pathogenesis of CIA by suppressing catabolic factor expression, proliferation of inflammatory immune cells and osteoclastogenesis. These effects were mediated via blockade of the NF-κB signalling pathway. Therefore, 3'-SL exerted prophylactic and therapeutic effects and could be a novel therapeutic agent for the treatment of RA.
- Published
- 2018
9. PDP-1 links the TGF-β and IIS pathways to regulate longevity, development, and metabolism.
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Sri Devi Narasimhan, Kelvin Yen, Ankita Bansal, Eun-Soo Kwon, Srivatsan Padmanabhan, and Heidi A Tissenbaum
- Subjects
Genetics ,QH426-470 - Abstract
The insulin/IGF-1 signaling (IIS) pathway is a conserved regulator of longevity, development, and metabolism. In Caenorhabditis elegans IIS involves activation of DAF-2 (insulin/IGF-1 receptor tyrosine kinase), AGE-1 (PI 3-kinase), and additional downstream serine/threonine kinases that ultimately phosphorylate and negatively regulate the single FOXO transcription factor homolog DAF-16. Phosphatases help to maintain cellular signaling homeostasis by counterbalancing kinase activity. However, few phosphatases have been identified that negatively regulate the IIS pathway. Here we identify and characterize pdp-1 as a novel negative modulator of the IIS pathway. We show that PDP-1 regulates multiple outputs of IIS such as longevity, fat storage, and dauer diapause. In addition, PDP-1 promotes DAF-16 nuclear localization and transcriptional activity. Interestingly, genetic epistasis analyses place PDP-1 in the DAF-7/TGF-β signaling pathway, at the level of the R-SMAD proteins DAF-14 and DAF-8. Further investigation into how a component of TGF-β signaling affects multiple outputs of IIS/DAF-16, revealed extensive crosstalk between these two well-conserved signaling pathways. We find that PDP-1 modulates the expression of several insulin genes that are likely to feed into the IIS pathway to regulate DAF-16 activity. Importantly, dysregulation of IIS and TGF-β signaling has been implicated in diseases such as Type 2 Diabetes, obesity, and cancer. Our results may provide a new perspective in understanding of the regulation of these pathways under normal conditions and in the context of disease.
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- 2011
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10. Molecular mechanisms and therapeutic interventions in sarcopenia
- Author
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Eun Soo Kwon, Ki Sun Kwon, and Sung Sup Park
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Aging ,Sarcopenia ,lcsh:Diseases of the musculoskeletal system ,Psychological intervention ,Disease ,Review Article ,Bioinformatics ,Muscle hypertrophy ,03 medical and health sciences ,Atrophy ,medicine ,Mechanisms ,Myogenesis ,business.industry ,Autophagy ,Skeletal ,medicine.disease ,musculoskeletal system ,body regions ,030104 developmental biology ,Therapy ,Stem cell ,lcsh:RC925-935 ,business ,human activities - Abstract
Sarcopenia is the degenerative loss of muscle mass and function with aging. Recently sarcopenia was recognized as a clinical disease by the International Classification of Disease, 10th revision, Clinical Modification. An imbalance between protein synthesis and degradation causes a gradual loss of muscle mass, resulting in a decline of muscle function as a progress of sarcopenia. Many mechanisms involved in the onset of sarcopenia include age-related factors as well as activity-, disease-, and nutrition-related factors. The stage of sarcopenia reflecting the severity of conditions assists clinical management of sarcopenia. It is important that systemic descriptions of the disease conditions include age, sex, and other environmental risk factors as well as levels of physical function. To develop a new therapeutic intervention needed is the detailed understanding of molecular and cellular mechanisms by which apoptosis, autophagy, atrophy, and hypertrophy occur in the muscle stem cells, myotubes, and/or neuromuscular junction. The new strategy to managing sarcopenia will be signal-modulating small molecules, natural compounds, repurposing of old drugs, and muscle-specific microRNAs.
- Published
- 2017
11. STAT5A-mediated NOX5-L expression promotes the proliferation and metastasis of breast cancer cells
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Eun-Soo Kwon, Jae Cheong Lim, Ki-Sun Kwon, Kwang-Pyo Lee, Dongjun Jeong, Ji Young Kim, So Hee Dho, and Chang-Jin Kim
- Subjects
0301 basic medicine ,Cell signaling ,Mice, Nude ,Biology ,STAT5A ,Metastasis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,STAT5 Transcription Factor ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,Promoter Regions, Genetic ,Cell Proliferation ,Mice, Inbred BALB C ,NADPH oxidase ,Cell growth ,Tumor Suppressor Proteins ,Mammary Neoplasms, Experimental ,Membrane Proteins ,NADPH Oxidases ,Cancer ,Cell Biology ,medicine.disease ,Antibodies, Neutralizing ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,NADPH Oxidase 5 ,Tumor progression ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Female ,Immunostaining - Abstract
NADPH oxidase (NOX) generates reactive oxygen species (ROS) and has been suggested to mediate cell proliferation in some cancers. Here, we show that an increase in the expression of NOX5 long form (NOX5-L) is critical for tumor progression in breast tumor tissues. Immunostaining of clinical samples indicated that NOX5 was overexpressed in 41.1% of breast ductal carcinoma samples. NOX5-L depletion consistently suppressed cell proliferation, invasion, and migration in vitro. Antibody-mediated neutralization of NOX5-L attenuated tumor progression in a mouse xenograft model. Promoter analysis revealed that NOX5-L expression is regulated by STAT5A in breast cancer cells. Based on our novel findings, we suggest that inhibition of NOX5-L may be a promising therapeutic strategy that exerts anti-cancer effects via the modulation of ROS-mediated cell signaling.
- Published
- 2017
12. A subset of microRNAs in the Dlk1-Dio3 cluster regulates age-associated muscle atrophy by targeting Atrogin-1
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Jae Young Lim, Young Hoon Son, Bora Lee, Kyung-Won Min, Eun Soo Kwon, Seung Min Lee, Yeon-Soo Kim, Yousin Suh, Je-Hyun Yoon, Yong Ryul Yang, Ju Yeon Kwak, Hak Chul Jang, Yeo Jin Shin, Ki Sun Kwon, Seokho Kim, Jeong Yi Choi, Kwang-Pyo Lee, Jae Sook Kang, and Seon-Kyu Kim
- Subjects
0301 basic medicine ,Untranslated region ,Sarcopenia ,lcsh:Diseases of the musculoskeletal system ,Cachexia ,Muscle aging ,Muscle Fibers, Skeletal ,MiR‐376c‐3p ,Iodide Peroxidase ,lcsh:QM1-695 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Atrophy ,Physiology (medical) ,microRNA ,Medicine ,Animals ,Humans ,Atrogin‐1 ,Orthopedics and Sports Medicine ,Dlk1‐Dio3 miRNA cluster ,business.industry ,Myogenesis ,Calcium-Binding Proteins ,Skeletal muscle ,Membrane Proteins ,lcsh:Human anatomy ,Original Articles ,medicine.disease ,Muscle atrophy ,Cell biology ,MicroRNAs ,Muscular Atrophy ,030104 developmental biology ,DLK1 ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Intercellular Signaling Peptides and Proteins ,Original Article ,lcsh:RC925-935 ,medicine.symptom ,business - Abstract
Background The microRNAs (miRNAs) down‐regulated in aged mouse skeletal muscle were mainly clustered within the delta‐like homologue 1 and the type III iodothyronine deiodinase (Dlk1‐Dio3) genomic region. Although clustered miRNAs are coexpressed and regulate multiple targets in a specific signalling pathway, the function of miRNAs in the Dlk1‐Dio3 cluster in muscle aging is largely unknown. We aimed to ascertain whether these miRNAs play a common role to regulate age‐related muscle atrophy. Methods To examine anti‐atrophic effect of miRNAs, we individually transfected 42 miRNA mimics in fully differentiated myotubes and analysed their diameters. The luciferase reporter assay using target 3′ untranslated region (UTR) and RNA pull‐down assay were employed to ascertain the target predicted by the TargetScan algorithm. To investigate the therapeutic potential of the miRNAs in vivo, we generated adeno‐associated virus (AAV) serotype 9 expressing green fluorescent protein (GFP) (AAV9‐GFP) bearing miR‐376c‐3p and infected it into the tibialis anterior muscle of old mice. We performed morphometric analysis and measured ex vivo isometric force using a force transducer. Human gluteus maximus muscle tissues (ages ranging from 25 to 80 years) were used to investigate expression levels of the conserved miRNAs in the Dlk1‐Dio3 cluster. Results We found that the majority of miRNAs (33 out of 42 tested) in the cluster induced anti‐atrophic phenotypes in fully differentiated myotubes with increasing their diameters. Eighteen of these miRNAs, eight of which are conserved in humans, harboured predicted binding sites in the 3′ UTR of muscle atrophy gene‐1 (Atrogin‐1) encoding a muscle‐specific E3 ligase. Direct interactions were identified between these miRNAs and the 3′ UTR of Atrogin‐1, leading to repression of Atrogin‐1 and thereby induction of eIF3f protein content, in both human and mouse skeletal muscle cells. Intramuscular delivery of AAV9 expressing miR‐376c‐3p, one of the most effective miRNAs in myotube thickening, dramatically ameliorated skeletal muscle atrophy and improved muscle function, including isometric force, twitch force, and fatigue resistance in old mice. Consistent with our findings in mice, the expression of miRNAs in the cluster was significantly down‐regulated in human muscle from individuals > 50 years old. Conclusions Our study suggests that genetic intervention using a muscle‐directed miRNA delivery system has therapeutic efficacy in preventing Atrogin‐1‐mediated muscle atrophy in sarcopenia.
- Published
- 2019
13. NADPH Oxidase 4 Contributes to Myoblast Fusion and Skeletal Muscle Regeneration
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Tae Hyun Youm, Sun-Hee Woo, Sung Sup Park, and Eun-Soo Kwon
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Aging ,Article Subject ,Pyridines ,Pyridones ,MyoD ,Cardiotoxins ,Biochemistry ,Myoblasts ,Mice ,Myoblast fusion ,Myosin ,medicine ,Animals ,Regeneration ,Myocyte ,Pyrazolones ,RNA, Small Interfering ,lcsh:QH573-671 ,Muscle, Skeletal ,Cells, Cultured ,Myogenin ,MyoD Protein ,Mice, Knockout ,Myosin Heavy Chains ,lcsh:Cytology ,Chemistry ,Myogenesis ,urogenital system ,Skeletal muscle ,Cell Differentiation ,Cell Biology ,General Medicine ,musculoskeletal system ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,NADPH Oxidase 4 ,cardiovascular system ,Pyrazoles ,RNA Interference ,Reactive Oxygen Species ,C2C12 ,tissues ,Research Article - Abstract
Myoblast fusion is an essential step in skeletal muscle development and regeneration. NADPH oxidase 4 (Nox4) regulates cellular processes such as proliferation, differentiation, and survival by producing reactive oxygen species (ROS). Insulin-like growth factor 1 induces muscle hypertrophy via Nox4, but its function in myoblast fusion remains elusive. Here, we report a ROS-dependent role of Nox4 in myoblast differentiation. Regenerating muscle fibers after injury by cardiotoxin had a lower cross-sectional area in Nox4-knockout (KO) mice than myofibers in wild-type (WT) mice. Diameters and fusion index values of myotubes differentiated from Nox4-KO primary myoblasts were significantly lower than those of myotubes derived from WT myoblasts. However, no difference was observed in the differentiation index and expression of MyoD, myogenin, and myosin heavy chain 3 (MHC) between KO and WT myotubes. The decreased fusion index was also observed during differentiation of primary myoblasts and C2C12 cells with suppressed Nox4 expression. In contrast, in C2C12 cells overexpressing Nox4, the fusion index was increased, whereas the differentiation index and MHC and myogenin protein expression were not affected compared to control. Interestingly, the expression of myomaker (Tmem8c), a fusogenic protein that controls myoblast fusion, was reduced in Nox4-knockdown C2C12 cells. The myomaker expression level was proportional to the cellular ROS level, which was regulated by of Nox4 expression level. These results suggests that Nox4 contributes to myoblast fusion, possibly through the regulation of myomaker expression via ROS production, and that Nox4-dependent ROS may promote skeletal muscle regeneration and growth.
- Published
- 2019
- Full Text
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14. Pancreatic adenocarcinoma up-regulated factor (PAUF) enhances the accumulation and functional activity of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer
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Ji Eun Baek, Yeon Jeong Kim, Song Cheol Kim, Seongyea Jo, Jinhoi Song, Dong-Uk Kim, Kwang-Pyo Lee, Yun-Yong Park, Jinsil Kim, Siyoung Yang, Jaemin Lee, Sang Seok Koh, Ki-Sun Kwon, Eun-Soo Kwon, Seokho Kim, Hee Jun Cho, Tae Heung Kang, and Suhwan Chang
- Subjects
0301 basic medicine ,medicine.medical_treatment ,MDSC ,pancreatic cancer ,medicine.disease_cause ,Metastasis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Pancreatic cancer ,Cell Line, Tumor ,Lectins ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Tumor microenvironment ,business.industry ,Myeloid-Derived Suppressor Cells ,Cancer ,Membrane Proteins ,Immunotherapy ,medicine.disease ,Pancreatic Neoplasms ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Myeloid-derived Suppressor Cell ,Adenocarcinoma ,Intercellular Signaling Peptides and Proteins ,Tumor Escape ,Carcinogenesis ,business ,PAUF ,Research Paper ,Carcinoma, Pancreatic Ductal - Abstract
// Jinhoi Song 1, 2, * , Jaemin Lee 1, * , Jinsil Kim 1, * , Seongyea Jo 1 , Yeon Jeong Kim 3 , Ji Eun Baek 3 , Eun-Soo Kwon 1 , Kwang-Pyo Lee 1 , Siyoung Yang 1 , Ki-Sun Kwon 1 , Dong-Uk Kim 1 , Tae Heung Kang 4 , Yun-Yong Park 5 , Suhwan Chang 6 , Hee Jun Cho 7 , Song Cheol Kim 8 , Sang Seok Koh 3 , Seokho Kim 1 1 Aging Research Institute, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea 2 Department of Biomolecular Science, University of Science and Technology, Daejeon, Republic of Korea 3 Department of Biological Sciences, Dong-A University, Busan, Republic of Korea 4 Department of Immunology, School of Medicine, Konkuk University, Seoul, Republic of Korea 5 Department of Biomedical Sciences and Physiology, University of Ulsan College of Medicine, Seoul, Republic of Korea 6 Departments of Biomedical Sciences and Physiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea 7 Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea 8 Department of Surgery, University of Ulsan College of Medicine & Asan Medical Center, Seoul, Republic of Korea * These authors have contributed equally to this work Correspondence to: Song-Cheol Kim, email: drksc@amc.seoul.kr Sang Seok Koh, email: sskoh@dau.ac.kr Seokho Kim, email: kims@kribb.re.kr Keywords: MDSC, PAUF, pancreatic cancer, tumor microenvironment Received: November 30, 2015 Accepted: May 28, 2016 Published: June 17, 2016 ABSTRACT Pancreatic cancer is characterized by an immunosuppressive tumor microenvironment (TME) with a profound immune infiltrate populated by a significant number of myeloid-derived suppressor cells (MDSCs). MDSCs have been increasingly recognized for their role in immune evasion and cancer progression as well as their potential as a target for immunotherapy. However, not much is known about the mechanisms regulating their behavior and function in the pancreatic TME. Here we report that pancreatic adenocarcinoma up-regulated factor (PAUF), a soluble protein involved in pancreatic tumorigenesis and metastasis, plays a role as an enhancer of tumor-infiltrating MDSC and its functional activity. We show that PAUF enhanced the accumulation of MDSCs in the spleen and tumor tissues of PAUF-overexpressing tumor cell-injected mice. In addition, PAUF was found to enhance the immunosuppressive function of MDSCs via the TLR4-mediated signaling pathway, which was demonstrated by PAUF-induced increased levels of arginase, nitric oxide (NO), and reactive oxygen species (ROS). The role of PAUF in modulating the functional properties of MDSCs was further demonstrated by the use of a PAUF-neutralizing antibody that caused a decreased number of tumor-infiltrating MDSCs and reduced MDSC immunosuppressive activity. The observations made in mice were confirmed in human pancreatic cancer patient-derived MDSCs, supporting the clinical relevance of our findings. Collectively, we conclude that the PAUF is a powerful and multifunctional promoter of tumor growth through increase and functional activation of MDSCs, suggesting therapeutic potential for targeting PAUF in pancreatic cancers.
- Published
- 2016
15. An Antibody Designed to Improve Adoptive NK-Cell Therapy Inhibits Pancreatic Cancer Progression in a Murine Model
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Kyungsu Kong, Janghwan Kim, Sang-Rae Lee, Seongyea Jo, Jaemin Lee, Wonbeak Yoo, Seokho Kim, Jeong-Yoon Kim, Duck Cho, Tae Heung Kang, Ji-Su Kim, Sun-Uk Kim, Hyunji Choi, and Eun-Soo Kwon
- Subjects
0301 basic medicine ,Cancer Research ,Immunoconjugates ,medicine.medical_treatment ,Immunology ,Immunotherapy, Adoptive ,Metastasis ,Cell therapy ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Cancer immunotherapy ,Pancreatic cancer ,Cell Line, Tumor ,medicine ,Animals ,Humans ,biology ,business.industry ,Chemotaxis ,Antibodies, Monoclonal ,Immunotherapy ,medicine.disease ,Combined Modality Therapy ,Xenograft Model Antitumor Assays ,Killer Cells, Natural ,Pancreatic Neoplasms ,Disease Models, Animal ,030104 developmental biology ,Treatment Outcome ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,biology.protein ,Disease Progression ,Female ,Antibody ,business - Abstract
Natural killer (NK) cells are primary immune cells that target cancer cells and can be used as a therapeutic agent against pancreatic cancer. Despite the usefulness of NK cells, NK-cell therapy is limited by tumor cell inhibition of NK-cell homing to tumor sites, thereby preventing a sustained antitumor immune response. One approach to successful cancer immunotherapy is to increase trafficking of NK cells to tumor tissues. Here, we developed an antibody-based NK-cell–homing protein, named NK-cell–recruiting protein-conjugated antibody (NRP-body). The effect of NRP-body on infiltration of NK cells into primary and metastatic pancreatic cancer was evaluated in vitro and in murine pancreatic ductal adenocarcinoma models. The NRP-body increased NK-cell infiltration of tumors along a CXCL16 gradient (CXCL16 is cleaved from the NRP-body by furin expressed on the surface of pancreatic cancer cells). CXCL16 induced NK-cell infiltration by activating RhoA via the ERK signaling cascade. Administration of the NRP-body to pancreatic cancer model mice increased tumor tissue infiltration of transferred NK cells and reduced the tumor burden compared with that in controls. Overall survival of NRP-body–treated mice (even the metastasis models) was higher than that of mice receiving NK cells alone. In conclusion, increasing NK-cell infiltration into tumor tissues improved response to this cancer immunotherapy. The combination of an NRP-body with NK-cell therapy might be useful for treating pancreatic cancer.
- Published
- 2018
16. 3'-Sialyllactose as an inhibitor of p65 phosphorylation ameliorates the progression of experimental rheumatoid arthritis
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Li-Jung, Kang, Eun-Soo, Kwon, Kwang Min, Lee, Chanmi, Cho, Jae-In, Lee, Young Bae, Ryu, Tae Hyun, Youm, Jimin, Jeon, Mi Ra, Cho, Seon-Yong, Jeong, Sang-Rae, Lee, Wook, Kim, and Siyoung, Yang
- Subjects
Arthritis, Rheumatoid ,Male ,Mice, Inbred C57BL ,Mice ,Mice, Inbred DBA ,Transcription Factor RelA ,Animals ,Oligosaccharides ,Phosphorylation ,Research Papers ,Cells, Cultured ,Research Paper - Abstract
Background and Purpose 3′‐Sialyllactose (3′‐SL) is a safe compound that is present in high levels in human milk. Although it has anti‐inflammatory properties and supports immune homeostasis, its effect on collagen‐induced arthritis (CIA) is unknown. In this study, we investigated the prophylactic and therapeutic effect of 3′‐SL on the progression of rheumatoid arthritis (RA) in in vitro and in vivo models. Experimental Approach The anti‐arthritic effect of 3′‐SL was analysed with fibroblast‐like synoviocytes in vitro and an in vivo mouse model of CIA. RT‐PCR, Western blotting and ELISA were performed to evaluate its effects in vitro. Histological analysis of ankle and knee joints of mice with CIA was performed using immunohistochemistry, as well as safranin‐O and haematoxylin staining. Key Results 3′‐SL markedly alleviated the severity of CIA in the mice by reducing paw swelling, clinical scores, incidence rate, serum levels of inflammatory cytokines and autoantibody production. Moreover, 3′‐SL reduced synovitis and pannus formation and suppressed cartilage destruction by blocking secretion of chemokines, pro‐inflammatory cytokines, https://en.wikipedia.org/wiki/Matrix_metalloproteinases and osteoclastogenesis via NF‐κB signalling. Notably, phosphorylation of p65, which is a key protein in the NF‐κB signalling pathway, was totally blocked by 3′‐SL in the RA models. Conclusions and Implications 3′‐SL ameliorated pathogenesis of CIA by suppressing catabolic factor expression, proliferation of inflammatory immune cells and osteoclastogenesis. These effects were mediated via blockade of the NF‐κB signalling pathway. Therefore, 3′‐SL exerted prophylactic and therapeutic effects and could be a novel therapeutic agent for the treatment of RA.
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- 2017
17. Bacteria-derived metabolite, methylglyoxal, modulates the longevity of C. elegans through TORC2/SGK-1/DAF-16 signaling.
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Min-Gi Shin, Jae-Woong Lee, Jun-Seok Han, Bora Lee, Jin-Hyuck Jeong, So-Hyun Park, Jong-Hwan Kim, Sumi Jang, Mooncheol Park, Seon-Young Kim, Seokho Kim, Yong Ryoul Yang, Jeong-Yoon Kim, Kwang-Lae Hoe, Chankyu Park, Kwang-Pyo Lee, Ki-Sun Kwon, and Eun-Soo Kwon
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CAENORHABDITIS elegans ,UNFOLDED protein response ,ADVANCED glycation end-products ,LONGEVITY ,PYRUVALDEHYDE - Abstract
Gut microbes play diverse roles in modulating host fitness, including longevity; however, the molecular mechanisms underlying their mediation of longevity remain poorly understood. We performed genome-wide screens using 3,792 Escherichia coli mutants and identified 44 E. coli mutants that modulated Caenorhabditis elegans longevity. Three of these mutants modulated C. elegans longevity via the bacterial metabolite methylglyoxal (MG). Importantly, we found that low MG-producing E. coli mutants, hns E. coli, extended the lifespan of C. elegans through activation of the DAF-16/FOXO family transcription factor and the mitochondrial unfolded protein response (UPRmt). Interestingly, the lifespan modulation by hns did not require insulin/insulin- like growth factor 1 signaling (IIS) but did require TORC2/SGK-1 signaling. Transcriptome analysis revealed that hns E. coli activated novel class 3 DAF-16 target genes that were distinct from those regulated by IIS. Taken together, our data suggest that bacteria-derived MG modulates host longevity through regulation of the host signaling pathways rather than through nonspecific damage on biomolecules known as advanced glycation end products. Finally, we demonstrate that MG enhances the phosphorylation of hSGK1 and accelerates cellular senescence in human dermal fibroblasts, suggesting the conserved role of MG in controlling longevity across species. Together, our studies demonstrate that bacteria-derived MG is a novel therapeutic target for aging and aging-associated pathophysiology. [ABSTRACT FROM AUTHOR]
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- 2020
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18. A new DAF-16 isoform regulates longevity
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Sri Devi Narasimhan, Eun-Soo Kwon, Heidi A. Tissenbaum, and Kelvin Yen
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Gene isoform ,Proto-Oncogene Proteins c-akt ,media_common.quotation_subject ,Longevity ,Active Transport, Cell Nucleus ,Context (language use) ,Article ,Animals, Genetically Modified ,Phosphatidylinositol 3-Kinases ,Daf-16 ,Animals ,Insulin ,Protein Isoforms ,Transgenes ,Insulin-Like Growth Factor I ,Caenorhabditis elegans ,Caenorhabditis elegans Proteins ,Promoter Regions, Genetic ,Transcription factor ,media_common ,Regulation of gene expression ,Genetics ,Multidisciplinary ,biology ,Superoxide Dismutase ,fungi ,Forkhead Transcription Factors ,biology.organism_classification ,Gene Expression Regulation ,Organ Specificity ,Mutation ,Signal Transduction ,Transcription Factors - Abstract
The insulin/IGF-1 signalling (IIS) pathway has diverse roles from metabolism to longevity1–5. In Caenorhabditis elegans, the single forkhead box O (FOXO) homologue, DAF-16, functions as the major target of the IIS pathway2,3,6,7. One of two isoforms4,5,8, DAF-16a, is known to regulate longevity, stress response and dauer diapause8–11. However, it remains unclear how DAF-16 achieves its specificity in regulating these various biological processes. Here we identify a new isoform, DAF-16d/f, as an important isoform regulating longevity. We show that DAF-16 isoforms functionally cooperate to modulate IIS-mediated processes through differential tissue enrichment, preferential modulation by upstream kinases, and regulating distinct and overlapping target genes. Promoter-swapping experiments show both the promoter and the coding region of DAF-16 are important for its function. Importantly, in mammals, four FOXO genes have overlapping and different functions6,12, and in C. elegans, a single FOXO/DAF-16 uses distinct isoforms to fine-tune the IIS-mediated processes in the context of a whole organism.
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- 2010
19. Gpx1 is a stationary phase-specific thioredoxin peroxidase in fission yeast
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Eun-Soo Kwon, Ji-Yoon Song, Jung-Hye Roe, and Si Young Lee
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GPX1 ,GPX3 ,Sulfite Reductase (Ferredoxin) ,Biophysics ,Biochemistry ,GPX6 ,Cytosol ,Glutathione Peroxidase GPX1 ,Gene Expression Regulation, Fungal ,Schizosaccharomyces ,Molecular Biology ,Aconitate Hydratase ,chemistry.chemical_classification ,Glutathione Peroxidase ,Base Sequence ,biology ,Glutathione peroxidase ,Peroxiredoxins ,Cell Biology ,biology.organism_classification ,Glutathione ,Mitochondria ,Oxidative Stress ,chemistry ,Mutation ,Schizosaccharomyces pombe ,biology.protein ,Electrophoresis, Polyacrylamide Gel ,Thioredoxin ,Peroxidase - Abstract
The genome sequence of Schizosaccharomyces pombe reveals only one gene for a putative glutathione peroxidase (gpx1(+)). The Gpx1 protein has a peroxidase activity but preferred thioredoxin to glutathione as an electron donor when examined in vitro and in vivo, and therefore is a thioredoxin peroxidase. Besides H(2)O(2), it can reduce alkyl and phospholipid hydroperoxides. Expression of the gpx1 gene was elevated at the stationary phase, and we found that it supported long-term survival of S. pombe. The mutant also exhibited some defect in the activity of aconitase, an oxidation-labile Fe-S enzyme in mitochondria. Activity of sulfite reductase, a labile Fe-S enzyme in the cytosol, was also dramatically lowered in the mutant in the stationary phase. The Gpx1 protein, without any obvious targeting sequence, was localized in mitochondria as well as in the cytosol. Therefore, Gpx1 must serve to ensure optimal mitochondrial function and cytosolic environment, especially in the stationary phase.
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- 2008
20. miR-431 promotes differentiation and regeneration of old skeletal muscle by targeting Smad4
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Yeo Jin Shin, Kwang-Pyo Lee, Ji Young Kim, Seung Min Lee, Su-Jin Baek, Seon-Young Kim, Jeong Yi Choi, Myriam Gorospe, Amaresh C. Panda, Eun-Soo Kwon, Ki-Sun Kwon, Young Jae Bahn, and Kotb Abdelmohsen
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Cellular differentiation ,Population ,Biology ,Muscle Development ,Cell Line ,Myoblasts ,Mice ,Cardiotoxin ,Genetics ,medicine ,Myocyte ,Animals ,Humans ,Regeneration ,education ,Muscle, Skeletal ,3' Untranslated Regions ,Cellular Senescence ,Smad4 Protein ,education.field_of_study ,Myogenesis ,Regeneration (biology) ,Skeletal muscle ,Gene Expression Regulation, Developmental ,Cell Differentiation ,Molecular biology ,Mice, Inbred C57BL ,MicroRNAs ,medicine.anatomical_structure ,Gene Knockdown Techniques ,Cell aging ,Developmental Biology ,Research Paper ,Protein Binding - Abstract
The myogenic capacity of myoblasts decreases in skeletal muscle with age. In addition to environmental factors, intrinsic factors are important for maintaining the regenerative potential of muscle progenitor cells, but their identities are largely unknown. Here, comparative analysis of microRNA (miRNA) expression profiles in young and old myoblasts uncovered miR-431 as a novel miRNA showing markedly reduced abundance in aged myoblasts. Importantly, elevating miR-431 improved the myogenic capacity of old myoblasts, while inhibiting endogenous miR-431 lowered myogenesis. Bioinformatic and biochemical analyses revealed that miR-431 directly interacted with the 3′ untranslated region (UTR) of Smad4 mRNA, which encodes one of the downstream effectors of TGF-β signaling. In keeping with the low levels of miR-431 in old myoblasts, SMAD4 levels increased in this myoblast population. Interestingly, in an in vivo model of muscle regeneration following cardiotoxin injury, ectopic miR-431 injection greatly improved muscle regeneration and reduced SMAD4 levels. Consistent with the finding that the mouse miR-431 seed sequence in the Smad4 3′ UTR is conserved in the human SMAD4 3′ UTR, inhibition of miR-431 also repressed the myogenic capacity of human skeletal myoblasts. Taken together, our results suggest that the age-associated miR-431 plays a key role in maintaining the myogenic ability of skeletal muscle with age.
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- 2015
21. NOX5-L can stimulate proliferation and apoptosis depending on its levels and cellular context, determining cancer cell susceptibility to cisplatin
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So Hee Dho, Ki-Sun Kwon, Ji Young Kim, Sung Sup Park, Jae Cheong Lim, and Eun-Soo Kwon
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Programmed cell death ,Lung Neoplasms ,Skin Neoplasms ,cisplatin ,Apoptosis ,Breast Neoplasms ,Bioinformatics ,Transfection ,c-Abl ,Cell Line, Tumor ,Neoplasms ,NOX5-L ,Medicine ,Humans ,Phosphorylation ,Protein kinase B ,Cell Proliferation ,chemistry.chemical_classification ,Cisplatin ,Reactive oxygen species ,NADPH oxidase ,biology ,business.industry ,Cell growth ,CREB ,Membrane Proteins ,NADPH Oxidases ,ROS ,Up-Regulation ,Oncology ,chemistry ,NADPH Oxidase 5 ,Cancer cell ,biology.protein ,Cancer research ,business ,Reactive Oxygen Species ,medicine.drug ,Research Paper - Abstract
The NADPH oxidase, NOX5, is known to stimulate cell proliferation in some cancers by generating reactive oxygen species (ROS). We show here that the long form of NOX5 (NOX5-L) also promotes cell death, and thus determines the balance of proliferation and death, in skin, breast and lung cancer cells. Moderate expression of NOX5-L induced cell proliferation accompanied by AKT and ERK phosphorylation, whereas an increase in NOX5-L above a certain threshold promoted cancer cell death accompanied by caspase-3 activation. Notably, cisplatin treatment increased NOX5-L levels through CREB activation and enhanced NOX5-L activity through augmentation of Ca2+ release and c-Abl expression, ultimately triggering ROS-mediated cancer cell death-a distinct pathway absent in normal cells. These results indicate that NOX5-L determines cellular responses in a concentration- and context-dependent manner.
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- 2015
22. Regulation and the role of Cu,Zn-containing superoxide dismutase in cell cycle progression of Schizosaccharomyces pombe
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Eun Soo Kwon, Jung-Hye Roe, Joonseok Cha, Joon Lee, and Dong Wook Kim
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Glutathione reductase ,Saccharomyces cerevisiae ,Biophysics ,Biology ,Biochemistry ,Gene Expression Regulation, Enzymologic ,Superoxide dismutase ,Gene Expression Regulation, Fungal ,Schizosaccharomyces ,Gene expression ,Molecular Biology ,DNA Primers ,Base Sequence ,Superoxide Dismutase ,Cell growth ,Cell Cycle ,Hydrogen Peroxide ,Cell Biology ,Cell cycle ,biology.organism_classification ,Molecular biology ,Kinetics ,Schizosaccharomyces pombe ,biology.protein ,Mitogen-Activated Protein Kinases ,Cytokinesis ,Plasmids - Abstract
Regulation and the role of the sod1 + gene encoding CuZnSOD were investigated in fission yeast Schizosaccharomyces pombe . The amount of sod1 + mRNA decreased in the stationary phase, consistent with the decrease in enzyme activity. The transcript increased by treatment with oxidants such as H 2 O 2 and menadione (MD). Induction by H 2 O 2 was rapid and transient, being dependent on Wis1–Spc1–Atf1 pathway of signal transduction, whereas induction by MD was slow and sustained longer, being independent of Wis1 pathway. Wis1 and Spc1 also turned out to down-regulate sod1 + gene at the stationary phase. Tetrad analysis following sod1 + gene disruption revealed that the sod1 Δ cells were not viable, even on rich media. Repression of the sod1 + gene expression by thiamine through nmt1 promoter resulted in the arrest of cell cycle progression following S phase, possibly between G 2 and cytokinesis. The current and previous observations that the viability of Schizosaccharomyces pombe cells, unlike Saccharomyces cerevisiae , critically depends on the action of oxidative defense enzymes in the cytosol, such as CuZnSOD and glutathione reductase, suggest that S. pombe can serve as a good model system to study the effect of oxidative stress on cell proliferation.
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- 2002
23. Transcriptional regulation of Caenorhabditis elegansFOXO/DAF-16 modulates lifespan
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Darryl Conte, Michael J. Gilchrist, Heidi A. Tissenbaum, Ankita Bansal, Haibo Liu, Lesley T. MacNeil, and Eun-Soo Kwon
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Genetics ,Gene isoform ,Aging ,Research ,media_common.quotation_subject ,Longevity ,fungi ,DAF-16/FOXO ,Biology ,biology.organism_classification ,Downregulation and upregulation ,C. elegans ,Daf-16 ,Transcriptional regulation ,GATA transcription factor ,Isoforms ,Transcription ,Transcription factor ,Caenorhabditis elegans ,media_common - Abstract
Background: Insulin/IGF-1 signaling plays a central role in longevity across phylogeny. In C. elegans, the forkhead box O (FOXO) transcription factor, DAF-16, is the primary target of insulin/IGF-1 signaling, and multiple isoforms of DAF-16 (a, b, and d/f) modulate lifespan, metabolism, dauer formation, and stress resistance. Thus far, across phylogeny modulation of mammalian FOXOs and DAF-16 have focused on post-translational regulation with little focus on transcriptional regulation. In C. elegans ,w e have previously shown that DAF-16d/f cooperates with DAF-16a to promote longevity. In this study, we generated transgenic strains expressing near-endogenous levels of either daf-16a or daf-16d/f, and examined temporal expression of the isoforms to further define how these isoforms contribute to lifespan regulation. Results: Here, we show that DAF-16a is sensitive both to changes in gene dosage and to alterations in the level of insulin/IGF-1 signaling. Interestingly, we find that as worms age, the intestinal expression of daf-16d/f but not daf-16a is dramatically upregulated at the level of transcription. Preventing this transcriptional upregulation shortens lifespan, indicating that transcriptional regulation of daf-16d/f promotes longevity. In an RNAi screen of transcriptional regulators, we identify elt-2 (GATA transcription factor) and swsn-1 (core subunit of SWI/SNF complex) as key modulators of daf-16d/f gene expression. ELT-2 and another GATA factor, ELT-4, promote longevity via both DAF-16a and DAF-16d/f while the components of SWI/SNF complex promote longevity specifically via DAF-16d/f. Conclusions: Our findings indicate that transcriptional control of C. elegans FOXO/daf-16 is an essential regulatory event. Considering the conservation of FOXO across species, our findings identify a new layer of FOXO regulation as a potential determinant of mammalian longevity and age-related diseases such as cancer and diabetes.
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- 2014
24. Peroxiredoxin 3 has a crucial role in the contractile function of skeletal muscle by regulating mitochondrial homeostasis
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Ki Sun Kwon, Eun Soo Kwon, Kwang-Pyo Lee, Yeo Jin Shin, Ji Young Kim, Sang Chul Park, Seung Min Lee, Young Jae Bahn, Sue Goo Rhee, Sung Chun Cho, Do Yeun Jeong, and Hyun Ae Woo
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Mitochondrial ROS ,Myoblasts, Skeletal ,Muscle Fibers, Skeletal ,Biology ,Mitochondrion ,medicine.disease_cause ,Biochemistry ,DNA, Mitochondrial ,GTP Phosphohydrolases ,Adenosine Triphosphate ,Physiology (medical) ,medicine ,Myocyte ,Animals ,Homeostasis ,Muscle Strength ,Muscle, Skeletal ,Cells, Cultured ,Homeodomain Proteins ,Mice, Knockout ,Myogenesis ,Skeletal muscle ,Cell Differentiation ,musculoskeletal system ,Cell biology ,Mitochondria, Muscle ,medicine.anatomical_structure ,mitochondrial fusion ,Peroxiredoxin ,Reactive Oxygen Species ,Oxidative stress ,Muscle Contraction - Abstract
Antioxidant systems against reactive oxygen species (ROS) are important factors in regulating homeostasis in various cells, tissues, and organs. Although ROS are known to cause to muscular disorders, the effects of mitochondrial ROS in muscle physiology have not been fully understood. Here, we investigated the effects of ROS on muscle mass and function using mice deficient in peroxiredoxin 3 (Prx3), which is a mitochondrial antioxidant protein. Ablation of Prx3 deregulated the mitochondrial network and membrane potential of myotubes, in which ROS levels were increased. We showed that the DNA content of mitochondria and ATP production were also reduced in Prx3-KO muscle. Of note, the mitofusin 1 and 2 protein levels decreased in Prx3-KO muscle, a biochemical evidence of impaired mitochondrial fusion. Contractile dysfunction was examined by measuring isometric forces of isolated extensor digitorum longus (EDL) and soleus muscles. Maximum absolute forces in both the EDL and the soleus muscles were not significantly affected in Prx3-KO mice. However, fatigue trials revealed that the decrease in relative force was greater and more rapid in soleus from Prx3-KO compared to wild-type mice. Taken together, these results suggest that Prx3 plays a crucial role in mitochondrial homeostasis and thereby controls the contractile functions of skeletal muscle.
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- 2014
25. Characterization of the Manganese-Containing Superoxide Dismutase and Its Gene Regulation in Stress Response of Schizosaccharomyces pombe
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Jung-Hye Roe, Jae-Hoon Jeong, and Eun-Soo Kwon
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Molecular Sequence Data ,Biophysics ,SOD2 ,Pancreatitis-Associated Proteins ,Mitochondrion ,Biochemistry ,Gene Expression Regulation, Enzymologic ,Superoxide dismutase ,Gene product ,chemistry.chemical_compound ,Osmotic Pressure ,Gene Expression Regulation, Fungal ,Schizosaccharomyces ,Amino Acid Sequence ,Molecular Biology ,Peptide sequence ,DNA Primers ,Regulation of gene expression ,Base Sequence ,biology ,Superoxide Dismutase ,Superoxide ,Cell Biology ,biology.organism_classification ,chemistry ,Schizosaccharomyces pombe ,biology.protein ,Subcellular Fractions - Abstract
Fission yeast Schizosaccharomyces pombe contains two superoxide dismutases (SODs), one in the cytosol and the other in mitochondria. The sod2+ gene encoding putative mitochondrial superoxide dismutase containing manganese (MnSOD) has been isolated. Purification and analysis of the sod2+ gene product revealed that it contained only manganese as a cofactor, thus verified to be a genuine MnSOD. It was localized in mitochondria as expected. Its N-terminal amino acid sequence indicated that the mitochondrial targeting sequence of 21 amino acids was removed. The native form consisted of two identical subunits. The sod2+ expression was induced by external stresses, such as treatments with superoxide generators, high osmolarity, and heat. The induction by these stress treatments depended on Wis1-Spc1 MAPK signal transduction pathway being independent of transcription factors Atf1 or Pap1. The sod2 disruption rendered cells sensitive to various superoxide-generators, heat, and high osmolarity, suggesting that the mitochondrial MnSOD acts as a general defense agent against multiple stresses.
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- 2001
26. CTHRC1 promotes angiogenesis by recruiting Tie2-expressing monocytes to pancreatic tumors
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Sang Seok Koh, Yeon Jeong Kim, Hee Jun Cho, Song Cheol Kim, Suhwan Chang, Yeonsil Hwang, Tae Heung Kang, Eun-Soo Kwon, Min Kyung Kang, Seongyea Jo, Jinhoi Song, Seokho Kim, Jaemin Lee, and Hosung Bae
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Angiogenesis ,Clinical Biochemistry ,Biology ,medicine.disease_cause ,Biochemistry ,Metastasis ,Neovascularization ,03 medical and health sciences ,0302 clinical medicine ,Pancreatic cancer ,medicine ,Molecular Biology ,Tube formation ,Tumor microenvironment ,medicine.disease ,Endothelial stem cell ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Original Article ,medicine.symptom ,Carcinogenesis - Abstract
CTHRC1 (collagen triple-helix repeat-containing 1), a protein secreted during the tissue-repair process, is highly expressed in several malignant tumors, including pancreatic cancer. We recently showed that CTHRC1 has an important role in the progression and metastasis of pancreatic cancer. Although CTHRC1 secretion affects tumor cells, how it promotes tumorigenesis in the context of the microenvironment is largely unknown. Here we identified a novel role of CTHRC1 as a potent endothelial activator that promotes angiogenesis by recruiting bone marrow-derived cells to the tumor microenvironment during tumorigenesis. Recombinant CTHRC1 (rCTHRC1) enhanced endothelial cell (EC) proliferation, migration and capillary-like tube formation, which was consistent with the observed increases in neovascularization in vivo. Moreover, rCTHRC1 upregulated angiopoietin-2 (Ang-2), a Tie2 receptor ligand, through ERK-dependent activation of AP-1 in ECs, resulting in recruitment of Tie2-expressing monocytes (TEMs) to CTHRC1-overexpressing tumor tissues. Treatment with a CTHRC1-neutralizing antibody-abrogated Ang-2 expression in the ECs in vitro. Moreover, administration of a CTHRC1-neutralizing antibody to a xenograft mouse model reduced the tumor burden and infiltration of TEMs in the tumor tissues, indicating that blocking the CTHRC1/Ang-2/TEM axis during angiogenesis inhibits tumorigenesis. Collectively, our findings support the hypothesis that CTHRC1 induction of the Ang-2/Tie2 axis mediates the recruitment of TEMs, which are important for tumorigenesis and can be targeted to achieve effective antitumor responses in pancreatic cancers.
- Published
- 2016
27. A homeobox protein Phx1 regulates long-term survival and meiotic sporulation in Schizosaccharomyces pombe
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Eun-Soo Kwon, Jung-Hye Roe, and Jiyoon Kim
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Microbiology (medical) ,Auxotrophy ,Molecular Sequence Data ,lcsh:QR1-502 ,Pancreatitis-Associated Proteins ,Homocitrate synthase ,Microbiology ,lcsh:Microbiology ,Fungal Proteins ,Gene Expression Regulation, Fungal ,Schizosaccharomyces ,Amino Acid Sequence ,Gene ,Transcription factor ,Fungal protein ,Microbial Viability ,biology ,Gene Expression Profiling ,Spores, Fungal ,biology.organism_classification ,Molecular biology ,Cell biology ,Schizosaccharomyces pombe ,biology.protein ,Homeobox ,Sequence Alignment ,Gene Deletion ,Research Article ,Transcription Factors - Abstract
Background In the fission yeast Schizosaccharomyces pombe, the phx1 + (pombe homeobox) gene was initially isolated as a multi-copy suppressor of lysine auxotrophy caused by depletion of copper/zinc-containing superoxide dismutase (CuZn-SOD). Overproduction of Phx1 increased the synthesis of homocitrate synthase, the first enzyme in lysine biosynthetic pathway, which is labile to oxidative stress. Phx1 has a well conserved DNA-binding domain called homeodomain at the N-terminal region and is predicted to be a transcription factor in S. pombe. However, its role has not been revealed in further detail. Here we examined its expression pattern and the phenotype of its null mutant to get clues on its function. Results Fluorescence from the Phx1-GFP expressed from a chromosomal fusion gene demonstrated that it is localized primarily in the nucleus, and is distinctly visible during the stationary phase. When we replaced the N-terminal homeobox domain of Phx1 with the DNA binding domain of Pap1, a well-characterized transcription factor, the chimeric protein caused the elevation of transcripts from Pap1-dependent genes such as ctt1 + and trr1 + , suggesting that Phx1 possesses transcriptional activating activity when bound to DNA. The amount of phx1 + transcripts sharply increased as cells entered the stationary phase and was maintained at high level throughout the stationary phase. Nutrient shift down to low nitrogen or carbon sources caused phx1 + induction during the exponential phase, suggesting that cells need Phx1 for maintenance function during nutrient starvation. The Δphx1 null mutant showed decreased viability in long-term culture, whereas overproduction of Phx1 increased viability. Decrease in long-term survival was also observed for Δphx1 under N- or C-starved conditions. In addition, Δphx1 mutant was more sensitive to various oxidants and heat shock. When we examined sporulation of the Δphx1/Δphx1 diploid strain, significant decrease in the formation of meiotic spores was observed. Conclusions Phx1 is a transcriptional regulator whose synthesis is elevated during stationary phase and by nutrient starvation in S. pombe. It supports long-term survival and stress tolerance against oxidation and heat, and plays a key role in the formation of meiotic spores.
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- 2012
28. PDP-1 links the TGF-β and IIS pathways to regulate longevity, development, and metabolism
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Eun-Soo Kwon, Srivatsan Padmanabhan, Kelvin Yen, Sri Devi Narasimhan, Heidi A. Tissenbaum, and Ankita Bansal
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Cancer Research ,Cell signaling ,Genetics and Genomics/Animal Genetics ,lcsh:QH426-470 ,Longevity ,Biology ,Receptor tyrosine kinase ,Receptor, IGF Type 1 ,Animals, Genetically Modified ,Developmental Biology/Developmental Molecular Mechanisms ,Genetics ,Animals ,Insulin ,Kinase activity ,Caenorhabditis elegans ,Caenorhabditis elegans Proteins ,Molecular Biology ,Transcription factor ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics ,fungi ,Gene Expression Regulation, Developmental ,Forkhead Transcription Factors ,Developmental Biology/Aging ,Receptor, Insulin ,Diabetes and Endocrinology ,Insulin receptor ,Crosstalk (biology) ,lcsh:Genetics ,Phenotype ,Pyruvate Dehydrogenase (Lipoamide)-Phosphatase ,Mutation ,biology.protein ,Phosphorylation ,RNA Interference ,Genetics and Genomics/Gene Discovery ,Signal transduction ,Receptors, Transforming Growth Factor beta ,Signal Transduction ,Transcription Factors ,Research Article - Abstract
The insulin/IGF-1 signaling (IIS) pathway is a conserved regulator of longevity, development, and metabolism. In Caenorhabditis elegans IIS involves activation of DAF-2 (insulin/IGF-1 receptor tyrosine kinase), AGE-1 (PI 3-kinase), and additional downstream serine/threonine kinases that ultimately phosphorylate and negatively regulate the single FOXO transcription factor homolog DAF-16. Phosphatases help to maintain cellular signaling homeostasis by counterbalancing kinase activity. However, few phosphatases have been identified that negatively regulate the IIS pathway. Here we identify and characterize pdp-1 as a novel negative modulator of the IIS pathway. We show that PDP-1 regulates multiple outputs of IIS such as longevity, fat storage, and dauer diapause. In addition, PDP-1 promotes DAF-16 nuclear localization and transcriptional activity. Interestingly, genetic epistasis analyses place PDP-1 in the DAF-7/TGF-β signaling pathway, at the level of the R-SMAD proteins DAF-14 and DAF-8. Further investigation into how a component of TGF-β signaling affects multiple outputs of IIS/DAF-16, revealed extensive crosstalk between these two well-conserved signaling pathways. We find that PDP-1 modulates the expression of several insulin genes that are likely to feed into the IIS pathway to regulate DAF-16 activity. Importantly, dysregulation of IIS and TGF-β signaling has been implicated in diseases such as Type 2 Diabetes, obesity, and cancer. Our results may provide a new perspective in understanding of the regulation of these pathways under normal conditions and in the context of disease., Author Summary Cells in the body respond to a variety of on/off signals that are relayed in a defined spatial and temporal manner. These signals influence several processes such as growth, fat storage, and the repair of damaged molecules. As humans age, the onset of diseases such as Type 2 Diabetes, obesity, and cancer often results from an imbalance in the levels of on/off signals in the cell. The insulin/IGF-1 signaling pathway is an important regulator of longevity, development, and metabolism across phylogeny. While the protein kinases that activate this pathway have been well studied, less is known about the protein phosphatases that tune down the signals. The roundworm C. elegans has been an excellent model system to study the role of insulin/IGF-1 signaling in the aging process. Here, we identify a new phosphatase that negatively regulates the insulin/IGF-1 pathway to enhance longevity and stress-resistance. Interestingly, the phosphatase achieves this function by tuning down the activity of a conserved TGF-β pathway, a pathway important for development. By reducing TGF-β pathway activity, this phosphatase decreases expression of insulin molecules that may stimulate the insulin/IGF-1 pathway. Our studies not only unravel a new regulator of these pathways, but also point to how they are more linked than previously thought. Both insulin/IGF-1 and TGF-β signaling have been implicated in age-associated diseases, and understanding their connection will provide us with potential therapeutic avenues.
- Published
- 2011
29. Inactivation of homocitrate synthase causes lysine auxotrophy in copper/zinc-containing superoxide dismutase-deficient yeast Schizosaccharomyces pombe
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Jung-Hye Roe, Eun-Soo Kwon, and Jae-Hoon Jeong
- Subjects
Auxotrophy ,Lysine ,Homocitrate synthase ,Biochemistry ,Superoxide dismutase ,chemistry.chemical_compound ,Schizosaccharomyces ,Cloning, Molecular ,Molecular Biology ,chemistry.chemical_classification ,biology ,Superoxide ,Superoxide Dismutase ,Oxo-Acid-Lyases ,Cell Biology ,biology.organism_classification ,Blotting, Northern ,Molecular biology ,Enzyme assay ,Culture Media ,Kinetics ,Enzyme ,chemistry ,Schizosaccharomyces pombe ,biology.protein ,Schizosaccharomyces pombe Proteins - Abstract
The fission yeast Schizosaccharomyces pombe lacking copper/zinc-containing superoxide dismutase (CuZn-SOD) is auxotrophic for lysine and sulfurous amino acids under aerobic growth conditions. A multicopy suppressor gene (phx1+) that restored the growth of CuZn-SOD-deficient cells on minimal medium was isolated. It encodes a putative DNA-binding protein with a conserved homeobox domain. Overproduction of Phx1 increased the amount of several proteins, and one of those turned out to be a putative homocitrate synthase (HCS) encoded by the lys4+ gene in S. pombe as judged by mass spectrometric analysis. Consistent with this observation, overexpression of the lys4+ gene increased HCS enzyme activity and was sufficient to suppress the lysine requirement of the CuZn-SOD-deficient cells. Enzyme activity and Western blot analyses revealed that the activity and protein level of HCS were dramatically reduced upon depletion of CuZn-SOD. Treatment of exponentially growing S. pombe cells with paraquat, a superoxide generator, caused a decrease in the amount of Lys4 protein as expected. These results led us to conclude that HCS, the first enzyme in the alpha-aminoadipate-mediated pathway for lysine synthesis common in fungi and some bacteria, is a labile target of oxidative stress caused by CuZn-SOD depletion and that its synthesis is positively regulated by the putative transcriptional regulator Phx1.
- Published
- 2005
30. Outcome of Chemotherapy with Pulmonary Tuberculosis Resistant to Isoniazid and Rifampin
- Author
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Hyun Cheol Ha, Su Hee Hwang, Eun Soo Kwon, and Seung Kyu Park
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Chemotherapy ,Univariate analysis ,Tuberculosis ,business.industry ,medicine.medical_treatment ,Isoniazid ,Retrospective cohort study ,medicine.disease ,Surgery ,Infectious Diseases ,Relative risk ,Internal medicine ,Cohort ,medicine ,Sputum ,medicine.symptom ,business ,medicine.drug - Abstract
Background : The treatment for multi-drug resistant tuberculosis(MDRTB) is encountered to be important clinically, but there are still a few reports about it all over the world. So, we evaluated the outcomes of only chemotherapy for the pulmonary MDRTB retrospectively. Method: We reviewed the clinical courses of 63 patients with pulmonary disease due to M.tuberculosis resistant to rifampin and isoniazid who were under follow-up between March 1996 and June 1996 after hospitalization at our hospital between January 1993 and January 1996. We performed cohort retrospective study for all these patient's records. Their regimens were selected individually and preferably included four medications that they had not been given previously and to which the strain was fully susceptible. Results: The 63 patients(mean age, 43.2 years) had previously received a median 5.1drugs. Fifty two(82.5%) patients responded to chemotherapy(as indicated by negative sputum cultures for at least three consecutive months) ; eleven patients(17.5 %) had no response, as shown by continually positive cultures. In a univariate analysis, an unfavorable response was significantly associated with greater number of resistant drugs before the current courses of therapy(relative risk 21.5 ; 95 percent confidence interval, 1.2-3.0; p
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- 1999
31. Clinical Finding of MDR Tuberculosis and Frequency of MOTT
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Sun Dae Song, Eun Soo Kwon, Hwa-Jung Kim, Mi Hee Bae, Cheon Tae Kim, and Cheol Min Kim
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Tuberculosis ,business.industry ,Significant difference ,Mean age ,medicine.disease ,MDR Tuberculosis ,Infectious Diseases ,Internal medicine ,Immunology ,Medicine ,Sputum ,medicine.symptom ,business - Abstract
Background : The frequency of MOTT has risen as the prevalence of tuberculosis has been declining. Our country has been also. The most of MOTT was resistant to the major anti-tuberculous drugs. Method : To compare clinical characteristics and frequencies of MDR tuberculosis with MOTT, the author studied 65 patients showing AFB culture positive with sputum. The data were collected from 176 patients who had been admitted at the National Masan Tuberculosis Hospital from May to June, 1997 to April, 1998. Result : The frequency of MDR tuberculosis was 43.1% and that of MOTT was 9.2%. Among 65 isolated mycobacteria, 3 cases were M. intracellulare. 2 cases were M. fortuitum, and 1 case was unidentified MOTT. The most frequent age group in 65 culture positive patients was 4th decade and the mean age was 44. The mean age was 61 in MOTT and 42 in M. tuberculosis and had significant difference(p
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- 1998
32. A Comparative Study of Effect of Secondary Anti-tuberculosis Drugs in the Retreatment of Pulmonary Tuberculosis
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Seung Kyu Park, Sun Dae Song, In Hwan Chio, Su Hee Hwang, Eun Soo Kwon, and Hyun Cheol Ha
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Infectious Diseases ,Anti tuberculosis ,business.industry ,Pulmonary tuberculosis ,Internal medicine ,medicine ,business ,Gastroenterology ,Surgery - Abstract
배 경 : 현재 우리나라에서 사용되어지고있는 여러 가지 재치료 결핵제재 조합의 치료효과를 비교함으로써 결핵 재치료시외 올바른 Regimen을 정립시키고자 실시하였다. 방 법 : 1994년 1월부터 1996년 11월까지 국립마산병원에 입원하였던 재치료 환자로서 2차약제를 처음 처방한 104명을 OFX+PTA+CS+PAS+Aminoglycoside주사제를 사용하는 처방군 48명과 PZA+PTA+CS+PAS+Aminoglycoside주사제를 사용하는 처방군 35명 그리고 PZA+OFX+PTA+PAS+Aminoglycoside주사제를 사용하는 처방군 21명으로 분류하여 일반적인 임상 특성 및 치료효과를 연구하였다. 결 과 : 연령분포는 전체적으로는 50세 이상이 36례(34.6%)로 가장 많았고 평균연령은 42.6세였다. 성별은 남자가 81례(77.9%)로 많았다. 동반질환이 있는 경우는 31례(29.8%)였고, 합병증이 있는 경우는 18례(17.3%), 가족력이 있는 경우는 29례(27.9%)로 나타났다. 초치료처방은 HERZ(S or K) 48례 (46.2%), HER(S or K) 41례(39.4%), 기타 15례(14.4%)의 순 이었으며, 입원전 항결핵 치료에서 규칙적으로 치료한 경우가 49례(47.1%)로 나타났다. 약제 내성검사결과 INH와 RFP 동시에 내성이 있는 경우가 68례 (65.4%)로 가장 많았고 RFP에 내성이 있는 경우는 12례(11.5%), INH에 내성이 있는 경우는 3례(2.9%)이었으며, 모든 약제에 감수성이 있는 경우도 3례(2.9%)이었다. 입원시 호소한 증상은 전체적으로 기침이 93례(89.4%)로 가장 많았고, 객담 72례(69.2%), 호흡곤란 39례(37.5%), 체중감소 35례(33.7%), 혈담 16례(15.4%)의 순 이었으며, 증상이 없는 경우도 1례(0.96%)있었다. 입원시 병변의 범위에 따른 분류는 전체적으로 중증이 73례(70.2%)로 가장 많았고 중등증 28례(26.9%), 경증 3례(2.9%)의 순 이었다. 약제에 대한 부작용용 위장장애 31례(29.8%), 관절통 22례(21.2%), 피부질환 12례(11.5%) 등의 순이었다. 객담도말검사상 균이 음전화된 경우는 89례(85.6%)로 Group I이 42례(87.5%), Group II가 28례(80.0%), Group III가 19례(90.5%)였고, 평균 균음전 기간은 4.0개월로 Group I이 4.0개월, Group II가 4.6개월, Group III가 3.0개월이었다. 결 론 : 재치료 병합치료에서 OFX는 PZA를 사용하지 못하는 환자에게 투여하여 PZA를 사용할 때와 유사한 결과를 얻었으며, CS를 사용할 수 없는 환자에게 OFX와 PZA를 복합 처방함으로써 좋은 결과를 얻을 수 있을 것으로 생각된다. 【Background : In the management of patients whose primary chemotherapy has failed, careful assessment is essential. It is important to find out as accurate a chemotherapy history as possible. Preferably it should contain the drugs which has never used before. The purpose of present study is establishment of retreatment regimen for pulmonary tuberculosis. The present report concerns the results of retreatment of pulmonary tuberculosis patients treated at National Masan Tuberculosis Hospital. Methods : Retrospective cohort study was made of 104 drug-resistant pulmonary tuberculosis patients who were treated by five regimens between Jan. 1994 and Nov. 1996. All the patients taken medicine for second anti-tuberculosis regimens for the first time. We separated the patients by three groups(Group I ; OFX+PTA+CS+PAS+Aminoglycoside, Group II : PZA+PTA+CS+PAS+Aminoglycoside, Group III : PZA+OFX+PTA+PAS+Aminoglycoside). Results : The age distribution was most frequent in fourth decade(36patients, 34.6%) and the mean age was 42.6 year. The sex distribution was more frequent in the males(81 patients, 85.7%). There was 31 patients(29.8%) with combined diseaes, 18 patients with complication and 24 patients(27.9%) with family history. Primary chemotherapy regimens were HERZ(S or K) in 48 patients (46.2%), HER(S or K) in 41 patients(39.4%) and others in 15 patients(14.4%). Result of drug sensitivity test showed that the resistance to INH and RFP is in 68 patients(65.4%), RFP is 12 patients(11.5%), INH is in 3 patients(2.9%) and all sensitive to INH and RFP is 3 patients(2.9%). The clinical symptoms on admission were coughing(89.4%), sputum(69.2%), dyspnea on exertion(37.5%), weight loss(33.7%) blood tinged sputum(15.4%) and others. The extent of disease on the radiograph was far-advanced in 73 patients(70.2%), moderate in 28 patients(26.9%) and minimal in 3 patients(2.9%). The side effects for drugs were gastrointestinal troubles in 31 patients(29.8%), arthralgia in 22 patients(21.2%), skin rash in 12 patients(11.5%) and others. The negative conversion rate on sputum AFB smear was 85.6%(87.5% in Group I, 80.0% in Group II and 90.5% in Group III). The average negative conversion time on sputum was 4 month(4.0 month in Group I, 4.6 month in Group II and 3.0 month in Group III). Conclusion : In the retreatment of pulmonary tuberculosis, ofloxacin is useful drug for the patients who are not available to use PZA and combination of PZA and OFX can be use effectively substituting for CS.】
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- 1998
33. Pulmonary Resection in the Treatment of Multidrug-Resistant Tuberculosis
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Eun Soo Kwon, Su Hee Hwang, Seung Kyu Park, Hung Yol Lee, Hyun Cheol Ha, and Sun Dae Song
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Chemotherapy ,Tuberculosis ,medicine.diagnostic_test ,biology ,business.industry ,medicine.medical_treatment ,Pulmonary disease ,medicine.disease ,biology.organism_classification ,Surgery ,Sputum culture ,Multiple drug resistance ,Mycobacterium tuberculosis ,Infectious Diseases ,medicine ,In patient ,Pulmonary resection ,business - Abstract
Background : Recent outbreaks of pulmonary disease due to drug-resistant strains of Mycobacterium Tuberculosis have resulted in significant morbidity and mortality in patients worldwide. We reviewed our experience to evaluate the effects of pulmonary resection on the management of multidrug-resistant tuberculosis. Method : A retrospective review was performed of 41 patients undergoing pulmonary resection for multidrug-resistant tuberculosis between January 1993 and December 1997. We divided these into 3 groups according to the radiologic findings : (1) patients who have reasonably localized lesion (Localized Lesion Group ; LLG) (2) patients who have cavitary lesions after pulmonary resection on chest roentgenogram (Remained Cavity Group : RCG) (3) patients who have Remained infiltrative lesions postoperatively (Remained infiltrative group : RIG). We evaluated the negative conversion rate after resection and overall response rate of the groups. Then they were compared with the results of the chemotherapy on the multi drug-resistant tuberculosis which has been outcome by Goble et al. Goble et al reported that negative conversion rate was 65% and overall response rate, 56% over a mean period of 5.1 months. Results : Seventy five point six percent were men and 24.4% women with a median age of 31 years (range, 16 to 60 years). Although the patients were treated preoperatively with multidrug regimens in an effort to reduce the mycobacterial burden, 22 of 41 were still sputum culture positive at the time of surgery. 20 of 22 patients(90.9%, p
- Published
- 1998
34. A homeobox protein Phx1 regulates long-term survival and meiotic sporulation in Schizosaccharomyces pombe.
- Author
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Ji-Yoon Kim, Eun-Soo Kwon, and Jung-Hye Roe
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GENES , *SCHIZOSACCHAROMYCES pombe , *PROTEINS , *AMINO acids , *OXIDATIVE stress - Abstract
Background: In the fission yeast Schizosaccharomyces pombe, the phx1+ (pombe homeobox) gene was initially isolated as a multi-copy suppressor of lysine auxotrophy caused by depletion of copper/zinc-containing superoxide dismutase (CuZn-SOD). Overproduction of Phx1 increased the synthesis of homocitrate synthase, the first enzyme in lysine biosynthetic pathway, which is labile to oxidative stress. Phx1 has a well conserved DNA-binding domain called homeodomain at the N-terminal region and is predicted to be a transcription factor in S. pombe. However, its role has not been revealed in further detail. Here we examined its expression pattern and the phenotype of its null mutant to get clues on its function. Results: Fluorescence from the Phx1-GFP expressed from a chromosomal fusion gene demonstrated that it is localized primarily in the nucleus, and is distinctly visible during the stationary phase. When we replaced the N-terminal homeobox domain of Phx1 with the DNA binding domain of Pap1, a well-characterized transcription factor, the chimeric protein caused the elevation of transcripts from Pap1-dependent genes such as ctt1+ and trr1+, suggesting that Phx1 possesses transcriptional activating activity when bound to DNA. The amount of phx1+ transcripts sharply increased as cells entered the stationary phase and was maintained at high level throughout the stationary phase. Nutrient shift down to low nitrogen or carbon sources caused phx1+ induction during the exponential phase, suggesting that cells need Phx1 for maintenance function during nutrient starvation. The Δphx1 null mutant showed decreased viability in long-term culture, whereas overproduction of Phx1 increased viability. Decrease in long-term survival was also observed for Δphx1 under N- or C-starved conditions. In addition, Δphx1 mutant was more sensitive to various oxidants and heat shock. When we examined sporulation of the Δphx1/Δphx1 diploid strain, significant decrease in the formation of meiotic spores was observed. Conclusions: Phx1 is a transcriptional regulator whose synthesis is elevated during stationary phase and by nutrient starvation in S. pombe. It supports long-term survival and stress tolerance against oxidation and heat, and plays a key role in the formation of meiotic spores. [ABSTRACT FROM AUTHOR]
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- 2012
- Full Text
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35. PDP-1 Links the TGF-β and IIS Pathways to Regulate Longevity, Development, and Metabolism.
- Author
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Narasimhan, Sri Devi, Yen, Kelvin, Bansal, Ankita, Eun-Soo Kwon, Padmanabhan, Srivatsan, and Tissenbaum, Heidi A.
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TRANSFORMING growth factors-beta ,LONGEVITY ,GENETIC regulation ,INSULIN-like growth factor-binding proteins ,DEVELOPMENTAL biology ,CAENORHABDITIS elegans ,ENZYME activation ,CELLULAR signal transduction - Published
- 2011
- Full Text
- View/download PDF
36. A new DAF-16 isoform regulates longevity.
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Eun-Soo Kwon, Narasimhan, Sri Devi, Yen, Kelvin, and Tissenbaum, Heidi A.
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- *
LONGEVITY , *METABOLISM , *INSULIN structure , *CAENORHABDITIS elegans , *FORKHEAD transcription factors , *DIAPAUSE , *TRANSGENE expression , *GENES , *MAMMALS - Abstract
The insulin/IGF-1 signalling (IIS) pathway has diverse roles from metabolism to longevity. In Caenorhabditis elegans, the single forkhead box O (FOXO) homologue, DAF-16, functions as the major target of the IIS pathway. One of two isoforms, DAF-16a, is known to regulate longevity, stress response and dauer diapause. However, it remains unclear how DAF-16 achieves its specificity in regulating these various biological processes. Here we identify a new isoform, DAF-16d/f, as an important isoform regulating longevity. We show that DAF-16 isoforms functionally cooperate to modulate IIS-mediated processes through differential tissue enrichment, preferential modulation by upstream kinases, and regulating distinct and overlapping target genes. Promoter-swapping experiments show both the promoter and the coding region of DAF-16 are important for its function. Importantly, in mammals, four FOXO genes have overlapping and different functions, and in C. elegans, a single FOXO/DAF-16 uses distinct isoforms to fine-tune the IIS-mediated processes in the context of a whole organism. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
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37. Inactivation of Homocitrate Synthase Causes Lysine Auxotrophy in Copper/Zinc-containing Superoxide.
- Author
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Eun-Soo Kwon, Jae-Hoon Jeong, and Jung-Hye Roe
- Subjects
- *
FISSION (Asexual reproduction) , *YEAST , *SCHIZOSACCHAROMYCES pombe , *SUPEROXIDE dismutase , *LYSINE , *AMINO acids , *CARRIER proteins , *ENZYMES - Abstract
The fission yeast Schizosaccharomyces pombe lacking copper/ zinc-containing superoxide dismutase (CuZn-SOD) is auxotrophic for lysine and sulfurous amino acids under aerobic growth conditions. A multicopy suppressor gene (phx1+) that restored the growth of CuZn-SOD-deficient cells on minimal medium was isolated. It encodes a putative DNA-binding protein with a conserved homeobox domain. Overproduction of Phx1 increased the amount of several proteins, and one of those turned out to be a putative homocitrate synthase (HCS) encoded by the lys4+ gene in S. pombe as judged by mass spectrometric analysis. Consistent with this observation, overexpression of the lys4+ gene increased HCS enzyme activity and was sufficient to suppress the lysine requirement of the CuZn-SOD-deficient cells. Enzyme activity and Western blot analyses revealed that the activity and protein level of HCS were dramatically reduced upon depletion of CuZn-SOD. Treatment of exponentially growing S. pombe cells with paraquat, a superoxide generator, caused a decrease in the amount of Lys4 protein as expected. These results led us to conclude that HCS, the first enzyme in the a-aminoadipate-mediated pathway for lysine synthesis common in fungi and some bacteria, is a labile target of oxidative stress caused by CuZn-SOD depletion and that its synthesis is positively regulated by the putative transcriptional regulator Phx1. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
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38. miR-431 promotes differentiation and regeneration of old skeletal muscle by targeting Smad4.
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Kwang-Pyo Lee, Yeo Jin Shin, Panda, Amaresh C., Abdelmohsen, Kotb, Ji Young Kim, Seung-Min Lee, Young Jae Bahn, Jeong Yi Choi, Eun-Soo Kwon, Su-Jin Baek, Seon-Young Kim, Gorospe, Myriam, and Ki-Sun Kwon
- Subjects
- *
MYOBLASTS , *SKELETAL muscle , *MUSCLES , *MYOGENESIS , *MICRORNA - Abstract
The myogenic capacity of myoblasts decreases in skeletal muscle with age. In addition to environmental factors, intrinsic factors are important for maintaining the regenerative potential of muscle progenitor cells, but their identities are largely unknown. Here, comparative analysis of microRNA (miRNA) expression profiles in young and old myoblasts uncovered miR-431 as a novel miRNA showing markedly reduced abundance in aged myoblasts. Importantly, elevating miR-431 improved the myogenic capacity of old myoblasts, while inhibiting endogenous miR-431 lowered myogenesis. Bioinformatic and biochemical analyses revealed that miR- 431 directly interacted with the 3' untranslated region (UTR) of Smad4 mRNA, which encodes one of the downstream effectors of TGF-β signaling. In keeping with the low levels of miR-431 in old myoblasts, SMAD4 levels increased in this myoblast population. Interestingly, in an in vivo model of muscle regeneration following cardiotoxin injury, ectopic miR-431 injection greatly improved muscle regeneration and reduced SMAD4 levels. Consistent with the finding that the mouse miR-431 seed sequence in the Smad4 3' UTR is conserved in the human SMAD4 3' UTR, inhibition of miR-431 also repressed the myogenic capacity of human skeletal myoblasts. Taken together, our results suggest that the age-associated miR-431 plays a key role in maintaining the myogenic ability of skeletal muscle with age. [ABSTRACT FROM AUTHOR]
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- 2015
- Full Text
- View/download PDF
39. If You Were Me 4
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(1976), Yoon Seong-ho, director, (1969), Kim Yong-Tae, director, Hyeon-seung, Lee, director, Gye-su, Jeon, director, (1965), Pang Eun-jin, director, Gun-ju, Lee, performer, Eun-soo, Son, performer, Bo-young, Park, performer, Dae-young, Jung, performer, Kun-hee, Hwang, performer, Eun-soo, Kwon, performer, Jung, Hwa-young, performer, and Nam, Ji-Hyun, performer
- Published
- 2008
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