28 results on '"Seung-Yon Lee"'
Search Results
2. Physiological notch signaling maintains bone homeostasis via RBPjk and Hey upstream of NFATc1.
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Xiaolin Tu, Jianquan Chen, Joohyun Lim, Courtney M Karner, Seung-Yon Lee, Julia Heisig, Cornelia Wiese, Kameswaran Surendran, Raphael Kopan, Manfred Gessler, and Fanxin Long
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Genetics ,QH426-470 - Abstract
Notch signaling between neighboring cells controls many cell fate decisions in metazoans both during embryogenesis and in postnatal life. Previously, we uncovered a critical role for physiological Notch signaling in suppressing osteoblast differentiation in vivo. However, the contribution of individual Notch receptors and the downstream signaling mechanism have not been elucidated. Here we report that removal of Notch2, but not Notch1, from the embryonic limb mesenchyme markedly increased trabecular bone mass in adolescent mice. Deletion of the transcription factor RBPjk, a mediator of all canonical Notch signaling, in the mesenchymal progenitors but not the more mature osteoblast-lineage cells, caused a dramatic high-bone-mass phenotype characterized by increased osteoblast numbers, diminished bone marrow mesenchymal progenitor pool, and rapid age-dependent bone loss. Moreover, mice deficient in Hey1 and HeyL, two target genes of Notch-RBPjk signaling, exhibited high bone mass. Interestingly, Hey1 bound to and suppressed the NFATc1 promoter, and RBPjk deletion increased NFATc1 expression in bone. Finally, pharmacological inhibition of NFAT alleviated the high-bone-mass phenotype caused by RBPjk deletion. Thus, Notch-RBPjk signaling functions in part through Hey1-mediated inhibition of NFATc1 to suppress osteoblastogenesis, contributing to bone homeostasis in vivo.
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- 2012
- Full Text
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3. The Effect of Customers Word-of-mouth Recommendation Intentions for Restaurants in Bangkok, Hong Kong, and Sydney
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Seung-yon Lee
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Word of mouth ,Advertising ,General Medicine ,Psychology - Published
- 2019
4. Author response for 'Gain‐of‐function Lrp5 Mutation Improves Bone Mass and Strength and Delays Hyperglycemia in a Mouse Model of Insulin‐Deficient Diabetes'
- Author
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Rocky Strollo, Nicola Napoli, Francesca Fontana, Céline Schott, Seung-Yon Lee, Maria S. Remedi, Malcolm Hamilton-Hall, Mathieu Ferron, Roberto Civitelli, Yael Alippe, and Giulia Leanza
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medicine.medical_specialty ,business.industry ,Insulin ,medicine.medical_treatment ,LRP5 ,medicine.disease ,Endocrinology ,Gain of function ,Diabetes mellitus ,Internal medicine ,Mutation (genetic algorithm) ,medicine ,business ,Bone mass - Published
- 2021
5. Gain-of-Function Lrp5 Mutation Improves Bone Mass and Strength and Delays Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes
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Rocky Strollo, Maria S. Remedi, Seung Yon Lee, Yael Alippe, Malcolm Hamilton-Hall, Nicola Napoli, Francesca Fontana, Céline Schott, Mathieu Ferron, Roberto Civitelli, and Giulia Leanza
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0301 basic medicine ,Male ,medicine.medical_specialty ,endocrine system ,Lrp5 ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,030209 endocrinology & metabolism ,White adipose tissue ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Bone Density ,Diabetes mellitus ,Internal medicine ,Brown adipose tissue ,medicine ,Diabetes Mellitus ,Animals ,Humans ,Insulin ,Orthopedics and Sports Medicine ,DIABETES ,Protein kinase B ,WNT SIGNALING ,business.industry ,Wnt signaling pathway ,LRP5 ,Original Articles ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Low Density Lipoprotein Receptor-Related Protein-5 ,chemistry ,Gain of Function Mutation ,Hyperglycemia ,Mutation ,Sclerostin ,BROWN ADIPOSE TISSUE ,Original Article ,business ,BONE ,hormones, hormone substitutes, and hormone antagonists - Abstract
High fracture rate and high circulating levels of the Wnt inhibitor, sclerostin, have been reported in diabetic patients. We studied the effects of Wnt signaling activation on bone health in a mouse model of insulin‐deficient diabetes. We introduced the sclerostin‐resistant Lrp5 A214V mutation, associated with high bone mass, in mice carrying the Ins2 Akita mutation (Akita), which results in loss of beta cells, insulin deficiency, and diabetes in males. Akita mice accrue less trabecular bone mass with age relative to wild type (WT). Double heterozygous Lrp5 A214V/Akita mutants have high trabecular bone mass and cortical thickness relative to WT animals, as do Lrp5 A214V single mutants. Likewise, the Lrp5 A214V mutation prevents deterioration of biomechanical properties occurring in Akita mice. Notably, Lrp5 A214V/Akita mice develop fasting hyperglycemia and glucose intolerance with a delay relative to Akita mice (7 to 8 vs. 5 to 6 weeks, respectively), despite lack of insulin production in both groups by 6 weeks of age. Although insulin sensitivity is partially preserved in double heterozygous Lrp5 A214V/Akita relative to Akita mutants up to 30 weeks of age, insulin‐dependent phosphorylated protein kinase B (pAKT) activation in vitro is not altered by the Lrp5 A214V mutation. Although white adipose tissue depots are equally reduced in both compound and Akita mice, the Lrp5 A214V mutation prevents brown adipose tissue whitening that occurs in Akita mice. Thus, hyperactivation of Lrp5‐dependent signaling fully protects bone mass and strength in prolonged hyperglycemia and improves peripheral glucose metabolism in an insulin independent manner. Wnt signaling activation represents an ideal therapeutic approach for diabetic patients at high risk of fracture. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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- 2021
6. 1964-P: Type 1 Diabetes: Sclerostin Resistance Improves Glucose Metabolism and Protects Bone Mass
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Seung-Yon Lee, Nicola Napoli, Rocky Strollo, Paolo Pozzilli, Giulia Leanza, Roberto Civitelli, and Yael Alippe
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endocrine system ,medicine.medical_specialty ,endocrine system diseases ,Endocrinology, Diabetes and Metabolism ,Carbohydrate metabolism ,medicine.disease ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Internal medicine ,Diabetes mellitus ,Internal Medicine ,medicine ,Sclerostin ,hormones, hormone substitutes, and hormone antagonists ,Bone mass - Abstract
Type 1 diabetes (T1D) is characterized by metabolic abnormalities and bone fragility. In humans and preclinical models of T1D, serum markers of bone formation are decreased suggesting reduced bone turnover rates. Moreover, circulating levels of the Wnt inhibitor sclerostin (Scl) are higher in T1D patients. To test the role of Scl in T1D bone disease, we introduced the Scl-resistant Lrp5A214V mutation, associated with high bone mass (HBM), in mice carrying the Ins2Akita mutation (Akita), which causes hypoinsulinemia and hyperglycemia at age 4-5 weeks. Although both Akita and Akita/HBM mutants developed diabetes (non-fasting blood glucose ≥300 mg/dl), they showed a very different onset timing. At 6 weeks, only 30% of Akita/HBM mice developed hyperglycemia, compared to 90% of Akita mice (n=10), with the majority of Akita/HBM mice becoming hyperglycemic by 12 weeks. At 6 weeks, Akita mice showed a significant impairment in glucose tolerance in an intraperitoneal glucose tolerance test (ipGTT) relative to mild glucose intolerance demonstrated in Akita/HBM mice (p Disclosure G. Leanza: None. Y. Alippe: None. S. Lee: None. R. Strollo: None. P. Pozzilli: None. R. Civitelli: Stock/Shareholder; Self; Amgen Inc., Eli Lilly and Company, Merck & Co., Inc. N. Napoli: None.
- Published
- 2019
7. Glucose metabolism induced by Bmp signaling is essential for murine skeletal development
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E. Dale Abel, Fanxin Long, and Seung-Yon Lee
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0301 basic medicine ,Male ,General Physics and Astronomy ,Bone Morphogenetic Protein 2 ,Bone Morphogenetic Protein 1 ,Mice ,Osteogenesis ,lcsh:Science ,Mice, Knockout ,Glucose Transporter Type 1 ,Multidisciplinary ,biology ,Chemistry ,Gene Expression Regulation, Developmental ,Cell Differentiation ,Cell biology ,medicine.anatomical_structure ,Female ,Chondrogenesis ,Signal Transduction ,Science ,Primary Cell Culture ,Cartilage metabolism ,Mechanistic Target of Rapamycin Complex 1 ,General Biochemistry, Genetics and Molecular Biology ,Chondrocyte ,Bone and Bones ,Article ,03 medical and health sciences ,Chondrocytes ,Downregulation and upregulation ,medicine ,Animals ,Endochondral ossification ,Bone Morphogenetic Protein Receptors, Type I ,Cell Proliferation ,Osteoblasts ,Cartilage ,Glucose transporter ,General Chemistry ,Embryo, Mammalian ,Hypoxia-Inducible Factor 1, alpha Subunit ,body regions ,030104 developmental biology ,Glucose ,Animals, Newborn ,biology.protein ,lcsh:Q ,GLUT1 - Abstract
Much of the mammalian skeleton originates from a cartilage template eventually replaced by bone via endochondral ossification. Despite much knowledge about growth factors and nuclear proteins in skeletal development, little is understood about the role of metabolic regulation. Here we report that genetic deletion of the glucose transporter Glut1 (Slc2a1), either before or after the onset of chondrogenesis in the limb, severely impairs chondrocyte proliferation and hypertrophy, resulting in dramatic shortening of the limbs. The cartilage defects are reminiscent to those caused by deficiency in Bmp signaling. Importantly, deletion of Bmpr1a in chondrocytes markedly reduces Glut1 levels in vivo, whereas recombinant BMP2 increases Glut1 mRNA and protein levels, boosting glucose metabolism in primary chondrocytes. Biochemical studies identify a Bmp-mTORC1-Hif1a signaling cascade resulting in upregulation of Glut1 in chondrocytes. The results therefore uncover a hitherto unknown connection between Bmp signaling and glucose metabolism in the regulation of cartilage development., It is unclear how metabolic regulation affects development of the skeleton. Here, the authors show that deletion of the glucose transporter Glut1 (Slc2a1) both prior to and following chondrogenesis in the mouse limb impairs chondrocyte proliferation and shortening of the limbs, modulated by BMP signaling.
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- 2018
8. How do economic, cultural, and global-connectedness distances moderate the effect of customers’ experiences on their intention to revisit non-indigenous restaurants? Evidence from Korean restaurants
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Renee Boyoung Kim, Jeoung Yul Lee, and Seung-yon Lee
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Economic distance ,Social connectedness ,05 social sciences ,Word of mouth ,Advertising ,Indigenous ,Country of origin ,Geography ,0502 economics and business ,Cultural distance ,050211 marketing ,Business and International Management ,Marketing ,050203 business & management - Abstract
In this study, we evaluate how the effect of customers' experiences on revisit intention for non-indigenous restaurants can be moderated by economic distance (ED), cultural distance (CD) and global-connectedness distance (GD) between the country of origin for a given non-indigenous restaurant and the customer’s resident country. Surveys were conducted in seven countries across three continents, and the levels of ED, CD and GD between Korea and the seven countries were used as moderators. The findings suggest that the types of food and staff are two elements that should be emphasized in countries that are relatively close to Korea. Conversely, elements like the atmosphere of the restaurant and word of mouth should be emphasized in countries that have greater distances from Korea. Of the three distances considered in the study, GD had the strongest moderating effect on the relationship between customers’ experiences and their intentions to return to the restaurant. As a whole, the results imply that...
- Published
- 2015
9. PTH Promotes Bone Anabolism by Stimulating Aerobic Glycolysis via IGF Signaling
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Emel Esen, Fanxin Long, Burton M. Wice, and Seung-Yon Lee
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medicine.medical_specialty ,Endocrinology ,Anabolism ,Anaerobic glycolysis ,Chemistry ,Endocrinology, Diabetes and Metabolism ,Internal medicine ,medicine ,Orthopedics and Sports Medicine ,Bone formation ,Glycolysis - Published
- 2015
10. SMILE upregulated by metformin inhibits the function of androgen receptor in prostate cancer cells
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Keesook Lee, Chaeyong Jung, Yuan-Bin Xie, Chin-Hee Song, Hueng-Sik Choi, and Seung-Yon Lee
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Male ,Transcriptional Activation ,Cancer Research ,medicine.medical_specialty ,Neoplasms, Hormone-Dependent ,Cell Growth Processes ,urologic and male genital diseases ,Mice ,Prostate cancer ,Transactivation ,Cell Line, Tumor ,Internal medicine ,Coactivator ,LNCaP ,medicine ,Animals ,Humans ,business.industry ,Prostatic Neoplasms ,medicine.disease ,Metformin ,Up-Regulation ,Androgen receptor ,Basic-Leucine Zipper Transcription Factors ,HEK293 Cells ,Endocrinology ,Oncology ,Nuclear receptor ,Receptors, Androgen ,business ,Corepressor ,medicine.drug - Abstract
Metformin, a diabetes drug, has been reported to inhibit the growth of prostate cancer cells. In this study, we investigated the effect and action mechanism of metformin on the function of androgen receptor (AR), a key molecule in the proliferation of prostate cancer cells. Metformin was found to reduce androgen-dependent cell growth and the expression of AR target genes by inhibiting AR function in prostate cancer cells such as LNCaP and C4-2 cells. Interestingly, metformin upregulated the protein level of small heterodimer partner-interacting leucine zipper (SMILE), a coregulator of nuclear receptors, and knockdown of SMILE expression with shRNA abolished the inhibitory effect of metformin on AR function. Further studies revealed that SMILE protein itself suppressed the transactivation of AR, and its ectopic expression resulted in the repressed expression of endogenous AR target genes, PSA and NKX3.1, in LNCaP cells. In addition, SMILE protein physically interacted with AR and competed with the AR coactivator SRC-1 to modulate AR transactivation. As expected, SMILE repressed androgen-dependent growth of LNCaP and C4-2 cells. Taken together, these results suggest that SMILE, which is induced by metformin, functions as a novel AR corepressor and may mediate the inhibitory effect of metformin on androgen-dependent growth of prostate cancer cells.
- Published
- 2014
11. Bmp Induces Osteoblast Differentiation through both Smad4 and mTORC1 Signaling
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Fanxin Long, Seung Yon Lee, and Courtney M. Karner
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0301 basic medicine ,animal structures ,Bone Morphogenetic Protein 2 ,Mechanistic Target of Rapamycin Complex 1 ,Biology ,Bone morphogenetic protein ,Bone morphogenetic protein 2 ,Mice ,Phosphatidylinositol 3-Kinases ,eIF-2 Kinase ,03 medical and health sciences ,Calcification, Physiologic ,medicine ,Animals ,Humans ,Proto-Oncogene Proteins c-abl ,Molecular Biology ,Transcription factor ,PI3K/AKT/mTOR pathway ,Smad4 Protein ,Osteoblasts ,Gene Expression Profiling ,TOR Serine-Threonine Kinases ,ATF4 ,Cell Differentiation ,Osteoblast ,Cell Biology ,Endoplasmic Reticulum Stress ,Activating Transcription Factor 4 ,Cell biology ,BMPR2 ,Wnt Proteins ,030104 developmental biology ,medicine.anatomical_structure ,Multiprotein Complexes ,Protein Biosynthesis ,embryonic structures ,Unfolded protein response ,Research Article ,Signal Transduction - Abstract
The bone morphogenetic protein (Bmp) family of secreted molecules has been extensively studied in the context of osteoblast differentiation. However, the intracellular signaling cascades that mediate the osteoblastogenic function of Bmp have not been fully elucidated. By profiling mRNA expression in the bone marrow mesenchymal progenitor cell line ST2, we discover that BMP2 induces not only genes commonly associated with ossification and mineralization but also genes important for general protein synthesis. We define the two groups of genes as mineralization related versus protein anabolism signatures of osteoblasts. Although it induces the expression of several Wnt genes, BMP2 activates the osteogenic program largely independently of de novo Wnt secretion. Remarkably, although Smad4 is necessary for the activation of the mineralization-related genes, it is dispensable for BMP2 to induce the protein anabolism signature, which instead critically depends on the transcription factor Atf4. Upstream of Atf4, BMP2 activates mTORC1 to stimulate protein synthesis, resulting in an endoplasmic reticulum stress response mediated by Perk. Thus, Bmp signaling induces osteoblast differentiation through both Smad4- and mTORC1-dependent mechanisms.
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- 2017
12. A Comparative Study on Orientation density to the Front and Path Length of Rotational Axis with/without Music during Fouette Turns
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Jae-Seok Ki, Chong-Gu Hah, Seong-Geun Oh, Hwa-Kyung Shin, Nam-Gyu Cho, Seung-Yon Lee, and Jae-Keun Park
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Angular momentum ,Path length ,Movement (music) ,Orientation (geometry) ,Geometry ,Rotational axis ,Sports biomechanics ,Trunk ,Mathematics ,Front (military) - Abstract
S, G. OH, Y. K. AHN, A Comparative Study on Orientation density of Head and Trunk to the Front with/without music during Fouette Turns. Korean Journal of Sport Biomechanics, Vol. 00, No. 0, pp. 00-00, 2013. Fouette turns are repeated pir- ouettes which begin as a normal pirouette en dehors but include a movement that allows the rotational momentum lost to friction to be regained once each revolution. The purpose of this study was to investigate on orientation density of head/trunk to the front with and without music to which dancers perform the Fouette turn in time. 10 female dancers(21.0±1.4 years old, height; 165.3±3.9 cm, weight: 50.5±5.7 kg) who are the students of S University participated in this study. It took shorter time to perform one revolution of fouette turn with music (930 ms) than without music (961 ms), which reason may be the shorter time of phase 2 in which the rotational momentum is not produced but lost to fiction. Orientation density of trunk to the front was smaller with music (.176) than without music (.196), while the one of head had not significant difference between with and without music. And the path length of marker on 2 nd left metatarsal bone during one revolution was smaller with music (35.7 cm) than without music (40.2 cm) but the difference was not statistically significant (p=.267).
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- 2013
13. Gene Expression Profile of Rat Prostate During Pubertal Growth and Maturation
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Soma Chattopadhyay, Eunsook Park, Keesook Lee, Seung-Yon Lee, and Eun-Yeung Gong
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Male ,medicine.medical_specialty ,Microarray ,medicine.drug_class ,Stimulation ,Biology ,Rats, Sprague-Dawley ,Prostate ,Cell Line, Tumor ,Internal medicine ,Gene expression ,medicine ,Animals ,Sexual maturity ,Sexual Maturation ,Fetus ,Gene Expression Profiling ,Gene Expression Regulation, Developmental ,Obstetrics and Gynecology ,Androgen ,Rats ,Gene expression profiling ,Endocrinology ,medicine.anatomical_structure ,Animals, Newborn - Abstract
Temporal gene expression profiling can provide valuable insight into mechanisms of differentiation and may be helpful in laying a foundation for characterization of the molecular aspects of development. Prostate development begins in fetal life and is complete at sexual maturity, and androgen stimulation is both necessary and sufficient for development and maturity of the prostate. In this study, we investigated gene expression profiles of rat prostate at 3 different developmental stages (2 weeks, 3.5 weeks, and 8 weeks), when serum testosterone levels are low, intermediate, and high. Through this analysis, we attempted to narrow down genes whose expression is affected by androgen increase during pubertal growth and maturation of the prostate.
- Published
- 2011
14. Synthesis and antifungal evaluation of 6-hydroxy-1H-carbazole-1,4(9H)-diones
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Jung An Hong, Seung-Yon Lee, Chung-Kyu Ryu, Aram Kim, Na Young Kim, and Joo Hee Yoon
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Antifungal Agents ,Clinical Biochemistry ,Carbazoles ,Pharmaceutical Science ,Microbial Sensitivity Tests ,Biochemistry ,Chemical synthesis ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,Organic chemistry ,Structure–activity relationship ,Phenols ,Molecular Biology ,chemistry.chemical_classification ,biology ,Carbazole ,Organic Chemistry ,Fungi ,Aromatic amine ,Fungi imperfecti ,Antimicrobial ,biology.organism_classification ,Quinone ,chemistry ,Molecular Medicine - Abstract
6-Hydroxy-1H-carbazole-1,4(9H)-diones were synthesized and tested for in vitro antifungal activity against two pathogenic strains of fungi. Among them tested, many compounds showed good antifungal activity. The results suggest that 6-hydroxy-1H-carbazole-1,4(9H)-diones would be potent antifungal agents.
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- 2011
15. Do VIP programs always work well? The moderating role of loyalty
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Seho Lee, Seung-yon Lee, Kyunghee Bu, and Donghoon Kim
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Marketing ,Work (electrical) ,Software deployment ,media_common.quotation_subject ,Loyalty ,Advertising ,Customer response ,Psychology ,Applied Psychology ,Consumer behaviour ,media_common - Abstract
This paper addresses some important issues involving the effective deployment of ever-increasing VIP program budgets. Recent research results on the effects of VIP programs have been somewhat mixed. Some studies have found a positive influence on consumer behavior, while others report no significant impact. The purpose of this research is to provide a possible explanation for such contradictory evidence in the literature. The results of this study reveal that customer responses to VIP programs depend on their loyalty traits. Specifically, two loyalty dimensions—behavioral loyalty and attitudinal loyalty—interact with each other in moderating the impact of VIP programs on customer response. A VIP program may produce positive results even for customers who are low in behavioral loyalty, with low spending levels, if their attitudinal loyalty is high. Conversely, such a program may not produce significant results even for high-spending customers if their attitudinal loyalty is not high enough. Thus, analysis that overlooks the moderating role of loyalty dimensions may have led to erroneous conclusions. Finally, at the managerial level, this paper points out the potential problems of relying solely on behavioral loyalty measures, such as purchase amount, in identifying VIP customers. © 2009 Wiley Periodicals, Inc.
- Published
- 2009
16. Determinants of visual forms used in print advertising
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Kyunghee Bu, Donghoon Kim, and Seung-yon Lee
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Marketing ,Print advertising ,Communication ,Advertising ,Psychology ,Cross-cultural studies - Abstract
Unlike past findings on cross-cultural advertising, culture seems to have little effect on visual forms in ads. In study 1, we tested whether the culture-congruent visual forms would still be preva...
- Published
- 2009
17. Rictor is required for optimal bone accrual in response to anti-sclerostin therapy in the mouse
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Yu Shi, Fanxin Long, Weiwei Sun, Seung-Yon Lee, and Wen-Chih Lee
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0301 basic medicine ,Male ,medicine.medical_specialty ,Aging ,Histology ,Stromal cell ,Physiology ,Endocrinology, Diabetes and Metabolism ,Osteoclasts ,Biology ,Antibodies ,Bone and Bones ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Osteoclast ,Osteogenesis ,Internal medicine ,medicine ,Animals ,Bone Resorption ,Adaptor Proteins, Signal Transducing ,Glycoproteins ,Mice, Knockout ,Osteoblasts ,Tibia ,RANK Ligand ,Wnt signaling pathway ,Osteoblast ,Organ Size ,X-Ray Microtomography ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Rapamycin-Insensitive Companion of mTOR Protein ,chemistry ,RANKL ,biology.protein ,Sclerostin ,Intercellular Signaling Peptides and Proteins ,Cortical bone ,Female ,Bone marrow ,Carrier Proteins ,Gene Deletion - Abstract
Wnt signaling has emerged as a major target pathway for the development of novel bone anabolic therapies. Neutralizing antibodies against the secreted Wnt antagonist sclerostin (Scl-Ab) increase bone mass in both animal models and humans. Because we have previously shown that Rictor-dependent mTORC2 activity contributes to Wnt signaling, we test here whether Rictor is required for Scl-Ab to promote bone anabolism. Mice with Rictor deleted in the early embryonic limb mesenchyme (Prx1-Cre;Rictorf/f, hereafter RiCKO) were subjected to Scl-Ab treatment for 5 weeks starting at 4 months of age. In vivo micro–computed tomography (μCT) analyses before the treatment showed that the RiCKO mice displayed normal trabecular, but less cortical bone mass than the littermate controls. After 5 weeks of treatment, Scl-Ab dose-dependently increased trabecular and cortical bone mass in both control and RiCKO mice, but the increase was significantly blunted in the latter. Dynamic histomorphometry revealed that the RiCKO mice formed less bone than the control in response to Scl-Ab. In addition, the RiCKO mice possessed fewer osteoclasts than normal under the basal condition and exhibited lesser suppression in osteoclast number by Scl-Ab. Consistent with the fewer osteoclasts in vivo, bone marrow stromal cells (BMSC) from the RiCKO mice expressed less Rankl but normal levels of Opg or M-CSF, and were less effective than the control cells in supporting osteoclastogenesis in vitro. The reliance of Rankl on Rictor appeared to be independent of Wnt-β-catenin or Wnt-mTORC2 signaling as Wnt3a had no effect on Rankl expression by BMSC from either control or RICKO mice. Overall, Rictor in the limb mesenchymal lineage is required for the normal response to the anti-sclerostin therapy in both bone formation and resorption.
- Published
- 2015
18. Notch signaling suppresses glucose metabolism in mesenchymal progenitors to restrict osteoblast differentiation.
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Seung-Yon Lee, Fanxin Long, Lee, Seung-Yon, and Long, Fanxin
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NOTCH signaling pathway , *GLUCOSE metabolism , *OSTEOBLASTS , *EMBRYOLOGY , *ADULTS , *SKELETON - Abstract
Notch signaling critically controls cell fate decisions in mammals, both during embryogenesis and in adults. In the skeleton, Notch suppresses osteoblast differentiation and sustains bone marrow mesenchymal progenitors during postnatal life. Stabilizing mutations of Notch2 cause Hajdu-Cheney syndrome, which is characterized by early-onset osteoporosis in humans, but the mechanism whereby Notch inhibits bone accretion is not fully understood. Here, we report that activation of Notch signaling by either Jagged1 or the Notch2 intracellular domain suppresses glucose metabolism and osteoblast differentiation in primary cultures of bone marrow mesenchymal progenitors. Importantly, deletion of Notch2 in the limb mesenchyme increases both glycolysis and bone formation in the long bones of postnatal mice, whereas pharmacological reduction of glycolysis abrogates excessive bone formation. Mechanistically, Notch reduces the expression of glycolytic and mitochondrial complex I genes, resulting in a decrease in mitochondrial respiration, superoxide production, and AMPK activity. Forced activation of AMPK restores glycolysis in the face of Notch signaling. Thus, suppression of glucose metabolism contributes to the mechanism, whereby Notch restricts osteoblastogenesis from bone marrow mesenchymal progenitors. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
19. ERα/E2 signaling suppresses the expression of steroidogenic enzyme genes via cross-talk with orphan nuclear receptor Nur77 in the testes
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Seung Chang Kim, CheMyong Ko, Keesook Lee, Seung Yon Lee, Ryun Sup Ahn, and Eunsook Park
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Male ,endocrine system ,medicine.medical_specialty ,Nerve growth factor IB ,medicine.drug_class ,Down-Regulation ,Mice, Transgenic ,Biochemistry ,Gene Expression Regulation, Enzymologic ,Transactivation ,Mice ,Endocrinology ,Cytochrome P-450 Enzyme System ,Genes, Reporter ,Internal medicine ,Testis ,medicine ,Nuclear Receptor Subfamily 4, Group A, Member 1 ,Animals ,Humans ,Testosterone ,Luciferases ,Promoter Regions, Genetic ,Molecular Biology ,Transcription factor ,Leydig cell ,Estradiol ,Chemistry ,Estrogen Receptor alpha ,Leydig Cells ,Receptor Cross-Talk ,Phosphoproteins ,Mice, Inbred C57BL ,medicine.anatomical_structure ,HEK293 Cells ,Nuclear receptor ,Estrogen ,Signal transduction ,Estrogen receptor alpha ,Protein Binding ,Signal Transduction - Abstract
Estrogen receptor alpha (ERα) has been reported to affect steroidogenesis in testicular Leydig cells, but its molecular mechanism remains unclear. Here, we investigate the effect of estrogen and ERα on Nur77, a major transcription factor that regulates the expression of steroidogenic enzyme genes. In MA-10 Leydig cells, estradiol (E2) treatment, and interestingly ERα overexpression, suppressed the cAMP-induced and Nur77-activated promoter activity of steroidogenic enzyme genes via the suppression of Nur77 transactivation. ERα physically interacted with Nur77 and inhibited its DNA binding activity. In addition, ERα/E2 signaling decreased Nur77 protein levels. Consistent with the above results, the testicular testosterone level was higher in Leydig cell-specific ERα knock-out mice (ERα(flox/flox)Cyp17iCre) than in wild-type mice (ERα(flox/flox)). Taken together, these results suggest that ERα/E2 signaling controls the Nur77-mediated expression of steroidogenic enzyme genes in Leydig cells. These findings may provide a mechanistic explanation for the local regulation of testicular steroidogenesis by estrogenic compounds and ERα.
- Published
- 2012
20. Physiological Notch Signaling Maintains Bone Homeostasis via RBPjk and Hey Upstream of NFATc1
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Manfred Gessler, Seung Yon Lee, Cornelia Wiese, Kameswaran Surendran, Fanxin Long, Joohyun Lim, Raphael Kopan, Jianquan Chen, Julia Heisig, Courtney M. Karner, and Xiaolin Tu
- Subjects
Cancer Research ,Anatomy and Physiology ,Cellular differentiation ,Mesoderm ,Mice ,0302 clinical medicine ,Molecular Cell Biology ,Basic Helix-Loop-Helix Transcription Factors ,Receptor, Notch2 ,Receptor, Notch1 ,Genetics (clinical) ,0303 health sciences ,Stem Cells ,Gene Expression Regulation, Developmental ,Cell Differentiation ,NFAT ,Osteoblast ,Cell biology ,medicine.anatomical_structure ,Immunoglobulin J Recombination Signal Sequence-Binding Protein ,030220 oncology & carcinogenesis ,Signal transduction ,Signal Transduction ,Research Article ,medicine.medical_specialty ,Histology ,lcsh:QH426-470 ,Mesenchyme ,Notch signaling pathway ,Embryonic Development ,Biology ,Cell fate determination ,Bone and Bones ,03 medical and health sciences ,Model Organisms ,Internal medicine ,Genetics ,medicine ,Animals ,Molecular Biology ,Transcription factor ,ddc:611 ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Osteoblasts ,NFATC Transcription Factors ,Repressor Proteins ,lcsh:Genetics ,Endocrinology ,Developmental Biology - Abstract
Notch signaling between neighboring cells controls many cell fate decisions in metazoans both during embryogenesis and in postnatal life. Previously, we uncovered a critical role for physiological Notch signaling in suppressing osteoblast differentiation in vivo. However, the contribution of individual Notch receptors and the downstream signaling mechanism have not been elucidated. Here we report that removal of Notch2, but not Notch1, from the embryonic limb mesenchyme markedly increased trabecular bone mass in adolescent mice. Deletion of the transcription factor RBPjk, a mediator of all canonical Notch signaling, in the mesenchymal progenitors but not the more mature osteoblast-lineage cells, caused a dramatic high-bone-mass phenotype characterized by increased osteoblast numbers, diminished bone marrow mesenchymal progenitor pool, and rapid age-dependent bone loss. Moreover, mice deficient in Hey1 and HeyL, two target genes of Notch-RBPjk signaling, exhibited high bone mass. Interestingly, Hey1 bound to and suppressed the NFATc1 promoter, and RBPjk deletion increased NFATc1 expression in bone. Finally, pharmacological inhibition of NFAT alleviated the high-bone-mass phenotype caused by RBPjk deletion. Thus, Notch-RBPjk signaling functions in part through Hey1-mediated inhibition of NFATc1 to suppress osteoblastogenesis, contributing to bone homeostasis in vivo., Author Summary Osteoporosis is a disease caused by disruption of the balance between bone formation and resorption resulting in a net loss of bone mass. Although anti-resorptive agents are the current mainstay of osteoporosis therapy, novel strategies to promote bone formation are critically needed for more effective prevention and treatment of the disease. Notch signaling, an evolutionally conserved mechanism among multi-cellular organisms, was recently shown to control bone formation and therefore represents a potential target pathway for novel bone-promoting therapeutics. In this study we elucidate the intracellular signaling mechanism through which Notch controls bone formation, providing a molecular framework that may guide future drug development.
- Published
- 2012
21. ROS inhibit the expression of testicular steroidogenic enzyme genes via the suppression of Nur77 transactivation
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Keon-Hee Kim, Jae Chun Ryu, Jung-Soo Han, Ho Zoon Chae, Keesook Lee, Eun-Yeung Gong, Seung-Yon Lee, Chul-Ho Yun, and Cheol Yi Hong
- Subjects
Male ,Transcriptional Activation ,Aging ,Nerve growth factor IB ,MAP Kinase Kinase 4 ,Proto-Oncogene Proteins c-jun ,Biology ,Biochemistry ,Gene Expression Regulation, Enzymologic ,Transactivation ,Mice ,Downregulation and upregulation ,Physiology (medical) ,Cell Line, Tumor ,Nuclear Receptor Subfamily 4, Group A, Member 1 ,Animals ,Cloning, Molecular ,RNA, Small Interfering ,Transcription factor ,Regulation of gene expression ,Anthracenes ,Kinase ,Leydig Cells ,Steroid 17-alpha-Hydroxylase ,Hydrogen Peroxide ,Phosphoproteins ,Molecular biology ,Oxidative Stress ,Mutation ,Phosphorylation ,Steroids ,Signal transduction ,Reactive Oxygen Species ,Protein Binding ,Signal Transduction - Abstract
Steroidogenesis decreases with aging in the testis, whereas the levels of reactive oxygen species (ROS) increase. In addition, ROS have been reported to inhibit testicular steroidogenesis. Here, we investigated the effects of ROS on the transcriptional activity of Nur77, one of the major transcription factors that regulate the expression of steroidogenic enzyme genes. ROS signaling inhibited Nur77 transactivation, which was diminished by either treatment with c-Jun N-terminal kinase (JNK) inhibitor or the expression of a dominant negative form of JNK. This suggests the involvement of JNK signaling, which elevates the expression of c-Jun as well as its phosphorylation in Leydig cells. In transient transfection assays, c-Jun suppressed Nur77 transactivation in a dose-dependent manner. Further studies using c-Jun mutants revealed that the protein level of c-Jun, but not phosphorylation itself, was important for the suppression of Nur77 transactivation. Nur77 directly interacted with c-Jun in vivo, which blocked the DNA binding activity of Nur77. Together, these results suggest that ROS signaling-mediated c-Jun upregulation suppresses the expression of steroidogenic enzyme genes by inhibiting Nur77 transactivation, resulting in the reduction of testicular steroidogenesis. These findings may provide a mechanistic explanation for the age-related decline in testicular steroid hormone production.
- Published
- 2009
22. Design, synthesis and evaluation of 2-phenyl-1H-benzo[d]imidazole-4,7-diones as vascular smooth muscle cell proliferation inhibitors
- Author
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Seung-Yon Lee, Sang Kook Lee, Ra-Young Lee, Chung-Kyu Ryu, Hwa-Jin Chung, and Kwang-Hoe Chung
- Subjects
Vascular smooth muscle ,Platelet-derived growth factor ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Chemical synthesis ,Muscle, Smooth, Vascular ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Drug Discovery ,medicine ,Myocyte ,Animals ,Molecular Biology ,Aorta ,Cells, Cultured ,Cell Proliferation ,Platelet-Derived Growth Factor ,Bicyclic molecule ,Chemistry ,Cell growth ,Organic Chemistry ,Molecular biology ,In vitro ,Growth Inhibitors ,Rats ,medicine.anatomical_structure ,Models, Chemical ,Drug Design ,Molecular Medicine ,Benzimidazoles ,Mitogen-Activated Protein Kinases ,Blood vessel - Abstract
A series of 2-phenyl-1H-benzo[d]imidazole-4,7-diones were synthesized and tested for their inhibitory activity on the PDGF-stimulated proliferation of rat aortic vascular smooth muscle cells. Among the tested compounds, 6-arylthio-5-chloro-2-phenyl-1H-benzo[d]imidazole-4,7-diones exhibited an potent antiproliferative activity.
- Published
- 2007
23. PTH Promotes Bone Anabolism by Stimulating Aerobic Glycolysis via IGF Signaling
- Author
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Fanxin Long, Burton M. Wice, Emel Esen, and Seung-Yon Lee
- Subjects
endocrine system ,medicine.medical_specialty ,Anabolism ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Parathyroid hormone ,Mechanistic Target of Rapamycin Complex 2 ,Protein Serine-Threonine Kinases ,Biology ,Article ,Bone and Bones ,Cell Line ,Immediate-Early Proteins ,Internal medicine ,Cyclic AMP ,medicine ,Teriparatide ,Animals ,Cell Lineage ,Orthopedics and Sports Medicine ,Glycolysis ,Insulin-Like Growth Factor I ,Carbon Isotopes ,Osteoblasts ,Tibia ,TOR Serine-Threonine Kinases ,Growth factor ,Cell Differentiation ,X-Ray Microtomography ,Carbon Dioxide ,Warburg effect ,Aerobiosis ,Mice, Inbred C57BL ,Citric acid cycle ,Glucose ,Endocrinology ,Animals, Newborn ,Parathyroid Hormone ,Anaerobic glycolysis ,Multiprotein Complexes ,hormones, hormone substitutes, and hormone antagonists ,Signal Transduction ,medicine.drug - Abstract
Teriparatide, a recombinant peptide corresponding to amino acids 1-34 of human parathyroid hormone (PTH), has been an effective bone anabolic drug for over a decade. However, the mechanism whereby PTH stimulates bone formation remains incompletely understood. Here we report that in cultures of osteoblast-lineage cells, PTH stimulates glucose consumption and lactate production in the presence of oxygen, a hallmark of aerobic glycolysis, also known as Warburg effect. Experiments with radioactively labeled glucose demonstrate that PTH suppresses glucose entry into the tricarboxylic acid cycle (TCA cycle). Mechanistically, the increase in aerobic glycolysis is secondary to insulin-like growth factor (Igf) signaling induced by PTH, whereas the metabolic effect of Igf is dependent on activation of mammalian target of rapamycin complex 2 (mTORC2). Importantly, pharmacological perturbation of glycolysis suppresses the bone anabolic effect of intermittent PTH in the mouse. Thus, stimulation of aerobic glycolysis via Igf signaling contributes to bone anabolism in response to PTH.
- Published
- 2015
24. Bmp Induces Osteoblast Differentiation through both Smad4 and mTORC1 Signaling.
- Author
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Karner, Courtney M., Seung-Yon Lee, and Fanxin Long
- Subjects
- *
BONE morphogenetic proteins , *OSTEOBLASTS , *CELL differentiation , *SMAD proteins , *MTOR protein - Abstract
The bone morphogenetic protein (Bmp) family of secreted molecules has been extensively studied in the context of osteoblast differentiation. However, the intracellular signaling cascades that mediate the osteoblastogenic function of Bmp have not been fully elucidated. By profiling mRNA expression in the bone marrow mesenchymal progenitor cell line ST2, we discover that BMP2 induces not only genes commonly associated with ossification and mineralization but also genes important for general protein synthesis. We define the two groups of genes as mineralization related versus protein anabolism signatures of osteoblasts. Although it induces the expression of several Wnt genes, BMP2 activates the osteogenic program largely independently of de novo Wnt secretion. Remarkably, although Smad4 is necessary for the activation of the mineralization-related genes, it is dispensable for BMP2 to induce the protein anabolism signature, which instead critically depends on the transcription factor Atf4. Upstream of Atf4, BMP2 activates mTORC1 to stimulate protein synthesis, resulting in an endoplasmic reticulum stress response mediated by Perk. Thus, Bmp signaling induces osteoblast differentiation through both Smad4- and mTORC1-dependent mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
25. Effects of the aqueous extract of Epimedii Herba on the induction of oral tolerance in mice
- Author
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Sook-Jung Im, Yeun-Ja Mun, Seung-Yon Lee, Joung-Hoon Kim, Sung-Won Lee, and Won-Hong Woo
- Subjects
Male ,Pharmaceutical Science ,Administration, Oral ,Pharmacology ,Mice ,Immune system ,Antigen ,Oral administration ,Drug tolerance ,medicine ,Animals ,Interferon gamma ,Mice, Inbred BALB C ,Phagocytes ,biology ,business.industry ,Plant Extracts ,General Medicine ,Drug Tolerance ,Plant Leaves ,stomatognathic diseases ,Ovalbumin ,Delayed hypersensitivity ,Immunology ,biology.protein ,Antibody ,business ,medicine.drug ,Drugs, Chinese Herbal - Abstract
We investigated the effects of the aqueous extract of Epimedii Herba (AEEH) on the induction of oral tolerance. Oral tolerance was induced in mice by giving an oral administration of 20 mg ovalbumin (OVA) 7 d before immunization with the antigen. AEEH at 40 mg/kg was given orally daily for 6 d from 24 h after the feeding of OVA. The results showed that oral administration of OVA greatly suppressed total serum and antigen-specific immunoglobulin (Ig) levels, phagocytic activity and delayed-type hypersensitivity (DTH) reaction to the antigen. The suppression of these immune responses to OVA by the oral antigen was associated with a marked reduction of the production of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) from spleen cells. However, AEEH treatment significantly blocked the suppression of total serum and antigen-specific IgG2a antibodies, phagocytic activity and DTH response by the oral OVA. The suppression of IFN-y production by the oral antigen was also greatly decreased by AEEH treatment. Therefore, AEEH appears to be effective in preventing the induction of oral tolerance to OVA.
- Published
- 2002
26. Dual function of Bmpr1a signaling in restricting preosteoblast proliferation and stimulating osteoblast activity in mouse.
- Author
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Joohyun Lim, Yu Shi, Karner, Courtney M., Seung-Yon Lee, Wen-Chih Lee, Guangxu He, and Fanxin Long
- Subjects
BONE morphogenetic proteins ,OSTEOBLASTS ,GROWTH factors ,BONE cells ,LABORATORY mice - Abstract
Exogenous bone morphogenetic proteins (Bmp) are well known to induce ectopic bone formation, but the physiological effect of Bmp signaling on normal bone is not completely understood. By deleting the receptor Bmpr1a in osteoblast lineage cells with Dmp1-Cre, we observed a dramatic increase in trabecular bone mass in postnatal mice, which was due to a marked increase in osteoblast number that was likely to be driven by hyperproliferation of Sp7
+ preosteoblasts. Similarly, inducible deletion of Bmpr1a in Sp7+ cells specifically in postnatal mice increased trabecular bone mass. However, deletion of Smad4 by the same approaches had only a minor effect, indicating that Bmpr1a signaling suppresses trabecular bone formation through effectors beyond Smad4. Besides increasing osteoblast number in the trabecular bone, deletion of Bmpr1a by Dmp1-Cre also notably reduced osteoblast activity, resulting in attenuation of periosteal bone growth. The impairment in osteoblast activity correlated with reduced mTORC1 signaling, whereas inhibition of mTORC1 activity in vivo abolished the induction of protein anabolism genes by BMP2 treatment . Thus, physiological Bmpr1a signaling in bone in vitro exerts a dual function in both restricting preosteoblast proliferation and promoting osteoblast activity. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF
27. Cucurbitacins fromTrichosanthes kirilowiias the Inhibitory Components on Tyrosinase Activity and Melanin Synthesis of B16/F10 Melanoma Cells
- Author
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Ho Sub Lee, Won-Hong Woo, Sook-Jung Im, Yeun-Ja Mun, Seung Yon Lee, Ho Joon Song, and Hyuncheol Oh
- Subjects
Stereochemistry ,Tyrosinase ,Pharmaceutical Science ,Trichosanthes ,Pharmacognosy ,Melanocyte ,Plant Roots ,Analytical Chemistry ,Melanin ,Inhibitory Concentration 50 ,Mice ,Cucurbitacins ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Animals ,Cucurbitacin D ,Melanoma ,Melanins ,Pharmacology ,Molecular Structure ,biology ,Monophenol Monooxygenase ,Plant Extracts ,Organic Chemistry ,Biological activity ,biology.organism_classification ,Antineoplastic Agents, Phytogenic ,Triterpenes ,medicine.anatomical_structure ,Complementary and alternative medicine ,Biochemistry ,Molecular Medicine ,Trichosanthes kirilowii - Abstract
Cucurbitacins 1 and 2 were isolated from the root of Trichosanthes kirilowii by tyrosinase inhibitory activity-guided fractionation. Spectroscopic analysis revealed that compounds 1 and 2 were cucurbitacin D and 23,24-dihydro-cucurbitacin D, respectively. Compounds 1 and 2 effectively inhibited the activity of tyrosinase (IC(50) = 0.18 microM and 6.7 microM, respectively), and the synthesis of melanin (IC(50) = 0.16 microM and 7.5 microM, respectively) in B16/F10 melanoma cells.
- Published
- 2002
28. Gene Expression Profile of Rat Prostate During Pubertal Growth and Maturation.
- Author
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Eun-Yeung Gong, Eunsook Park, Soma Chattopadhyay, Seung-Yon Lee, and Keesook Lee
- Subjects
GENE expression ,GENETIC regulation ,PROSTATE ,ANDROGENS ,GENES - Abstract
Temporal gene expression profiling can provide valuable insight into mechanisms of differentiation and may be helpful in laying a foundation for characterization of the molecular aspects of development. Prostate development begins in fetal life and is complete at sexual maturity, and androgen stimulation is both necessary and sufficient for development and maturity of the prostate. In this study, we investigated gene expression profiles of rat prostate at 3 different developmental stages (2 weeks, 3.5 weeks, and 8 weeks), when serum testosterone levels are low, intermediate, and high. Through this analysis, we attempted to narrow down genes whose expression is affected by androgen increase during pubertal growth and maturation of the prostate. [ABSTRACT FROM PUBLISHER]
- Published
- 2011
- Full Text
- View/download PDF
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