• International Journal of Oncology
• /
• v.56 no.1
• /
• pp.368-378
• /
• 2020

Meridianin C is a marine natural product with anticancer activity. Several meridianin C derivatives (compounds 7a-j) were recently synthesized, and their inhibitory effects on pro-viral integration site for Moloney murine leukemia virus (PIM) kinases, as well as their antiproliferative effects on human leukemia cells, were reported. However, the anti-leukemic effects and mechanisms of action of meridianin C and its derivatives remain largely unknown. The aim of the present study was to investigate the effects of meridianin C and its derivatives on MV4-11 human acute myeloid leukemia cell growth. The parent compound meridianin C did not markedly affect the viability and survival of MV4-11 cells. By contrast, MV4-11 cell viability and survival were reduced by meridianin C derivatives, with compound 7a achieving the most prominent reduction. Compound 7a notably inhibited the expression and activity of PIM kinases, as evidenced by reduced B-cell lymphoma-2 (Bcl-2)-associated death promoter phosphorylation at Ser112. However, meridianin C also suppressed PIM kinase expression and activity, and the pan-PIM kinase inhibitor AZD1208 only slightly suppressed the survival of MV4-11 cells. Thus, the anti-survival effect of compound 7a on MV4-11 cells was unrelated to PIM kinase inhibition. Moreover, compound 7a induced apoptosis, caspase-9 and -3 activation and poly(ADP-ribose) polymerase (PARP) cleavage, but did not affect death receptor (DR)-4 or DR-5 expression in MV4-11 cells. Compound 7a also induced the generation of cleaved Bcl-2, and the downregulation of myeloid cell leukemia (Mcl)-1 and X-linked inhibitor of apoptosis (XIAP) in MV4-11 cells. Furthermore, compound 7a increased eukaryotic initiation factor (eIF)-2α phosphorylation and decreased S6 phosphorylation, whereas GRP-78 expression was unaffected. Importantly, treatment with a pan-caspase inhibitor (z-VAD-fmk) significantly attenuated compound 7a-induced apoptosis, caspase-9 and -3 activation, PARP cleavage, generation of cleaved Bcl-2 and downregulation of Mcl-1 and XIAP in MV4-11 cells. Collectively, these findings demonstrated the strong anti-survival and pro-apoptotic effects of compound 7a on MV4-11 cells through regulation of caspase-9 and -3, Bcl-2, Mcl-1, XIAP, eIF-2α and S6 molecules.

• Tuberculosis and Respiratory Diseases
• /
• v.87 no.4
• /
• pp.494-504
• /
• 2024

Background: Ubiquitin C-terminal hydrolase L1 (UCHL1), which encodes thiol protease that hydrolyzes a peptide bond at the C-terminal glycine residue of ubiquitin, regulates cell differentiation, proliferation, transcriptional regulation, and numerous other biological processes and may be involved in lung cancer progression. UCHL1 is mainly expressed in the brain and plays a tumor-promoting role in a few cancer types; however, there are limited reports regarding its role in lung cancer. Methods: Single-cell RNA (scRNA) sequencing using 10X chromium v3 was performed on a paired normal-appearing and tumor tissue from surgical specimens of a patient who showed unusually rapid progression. To validate clinical implication of the identified biomarkers, immunohistochemical (IHC) analysis was performed on 48 non-small cell lung cancer (NSCLC) tissue specimens, and the correlation with clinical parameters was evaluated. Results: We identified 500 genes overexpressed in tumor tissue compared to those in normal tissue. Among them, UCHL1, brain expressed X-linked 3 (BEX3), and midkine (MDK), which are associated with tumor growth and progression, exhibited a 1.5-fold increase in expression compared to that in normal tissue. IHC analysis of NSCLC tissues showed that only UCHL1 was specifically overexpressed. Additionally, in 48 NSCLC specimens, UCHL1 was specifically upregulated in the cytoplasm and nuclear membrane of tumor cells. Multivariable logistic analysis identified several factors, including smoking, tumor size, and high-grade dysplasia, to be typically associated with UCHL1 overexpression. Survival analyses using The Cancer Genome Atlas (TCGA) datasets revealed that UCHL1 overexpression is substantially associated with poor survival outcomes. Furthermore, a strong association was observed between UCHL1 expression and the clinicopathological features of patients with NSCLC. Conclusion: UCHL1 overexpression was associated with smoking, tumor size, and high-grade dysplasia, which are typically associated with a poor prognosis and survival outcome. These findings suggest that UCHL1 may serve as an effective biomarker of NSCLC.

• Clinical and Experimental Pediatrics
• /
• v.49 no.9
• /
• pp.977-982
• /
• 2006

Purpose : There has been an increasing amount of literature concerning the association between Mycoplasma pneumoniae and asthma pathogenesis. Interleukin(IL)-6 stimulates the differentiation of monocytes, and can promote Th2 differentiation and simultaneously inhibit Th1 polarization. IL-8 is a potent chemoattractant and, it has been suggested, has a role in asthma pathogenesis. Nitric oxide (NO) synthesized by airway epithelium may be important in the regulation of airway inflammation and reactivity. Vascular endothelial growth factor(VEGF) has been reported to be a mediator of airway remodeling in asthma. We investigated the effects of M. pneumoniae on IL-6, IL-8, NO and VEGF production in human respiratory epithelial cells. Methods : A549 cells were cultured and inoculated with M. pneumoniae at a dose of 20 cfu/cell. After infection, the presence of M. pneumoniae in epithelial cell cultures was monitored by immunofluorescence and confirmed by polymerase chain reaction(PCR) detection. IL-6, IL-8 and VEGF were determined by an enzyme-linked immunosorbent assay and reverse transcriptase-polymerase chain reaction. NO was measured using the standard Griess reaction. Results : In A549 cells, M. pneumoniaeinduced IL-6, IL-8, NO and VEGF release in time-dependent manners. It also induced mRNA expression of IL-6, IL-8 and VEGF in similar manners. Conclusion : These observations suggest that M. pneumoniae might have a role in the pathogenesis of the allergic inflammation of bronchial asthma.

• Journal of the Korean Geographical Society
• /
• v.30 no.1
• /
• pp.35-56
• /
• 1995

During the last two decades, Korea has achieved remarkable economic growth. In this process the nation has become urbanized and industrialized. But we have also encountered widening regional disparity, housing shortage of larger cities, transportation congestion, environmental pollution and many other problems. Rapid increasing urbanization and continuous migration toward Seoul since the late 1960s have been one of the major concerns of government. Government has sought ways to moderate the population increase in Seoul. The regulation which include new town development near Seoul and dispersion strategies of higher education and other administration and living facilities outside of Seoul havemade a great expansion of the spatial influence of Seoul city. Seoul metropolitan reaion has evolved as the most powerful center of political and economical spaces. Generally within a metropolitan region, there exists a growing mutual interdependence economically, as well as socially between a central city and its surrounding area. Seoul metropolitan region manifests itself not only as a coherent system of urbanized regions, but also as an integral part of the daily urban system. The surrounding Gyunggi province and Seoul city become closely linked both economically and functionally, constituting true functlonai urban system. This study is primarily undertaken with the purpose of delineation of the sphere of influence of Seoul city in 1990. At the time of 1985, Seoul metropolitan region was delineated according to the result of the study which was performed by Korea Research Institute for Human Settlements. Afterward, the rapid speed of metropolitanization process with dramatic increase in mobility through the provision of wider transportation system across the Capital region have evolved, resulting in the great expansion of the spatial influence of Seoul city. So this study examines the expanded area of Seoul metropolitan regin during the period of 1985-90. In order to delineate Seoul metropolitan region, the indices of urbanization and functional linkage are selected. Variables included in the measurement of the urbanization level are agricultural structure, population characteristics, manufacturing and service industries, and cultural aspects such as newspaper circulation, the ratio of car ownership and piped water supply. Variables included in the measurement of functional linkage are commuting, shopping pattern, centralized service such as medical facilities and trade of agricultural products. The standardization method and factor analysis are employed in making the delineation of Seoul metropolitan region. According to the result of this study, 2 cities, 8 Eups and 46 Myuns are included Seoul metropolitan region in 1990. If we compare this delineated area in 1990 to that of 1985, we can find the distinctive pattern of expanded axes according to the main transportation routes such as Seoul-Suweon, Seoul-Gwangju, Seoul-Incheon. In 199O, all the Gyunggi province, except a few Myuns located at the north and northwest part of Gyunggi province, are included in Seoul metropolitan region. Furthermore, this study attempts to the analysis of regional structure of Seoul metropolitan region according to the functional characteristics of each city and Gun. Variables included in this analysis are the new residential function, manufacturing function, service function, education and infermation function, public facility function and agricultural function. Factor analysis and cluster analysis are employed in making regionalization. Seoul metropolitan reaion is subdivided into four subregions which reflect different functional specialization. The first group is the specialized region of newly formed residential function. The second group is the specialized reaion of manufacturing function. The third group is the specialized region of service function. And the fourth group has little specialized in terms of manufacturing, service, and residential function. But this region has some potentiality of development when Seoul metropolitan region grow continuously. Seoul metropolitan region accounted for 43% of national population, despite 11.8% of national land size in 1990. Although Seoul metropolitan region enjoys important agglomeration economies, it also has huge social cost in the form of transportation congestion, housing shortage, rapid increase of land value, environment pollution, and etc. Efficient metropolitan plan making is a vital element in promoting Seoul's economic development and providing high quality living environment at low cost. In the light of the result of this study, the outer ring of Seoul metropolitan region, especially northeastern part, are underdeveloped compared to overdeveloped southwestern area. It is needed to develop the guidelines for the implement of the growth control and management plan, inducing more balanced development for whole Seoul metropolitan reaion.

• Journal of Life Science
• /
• v.23 no.6
• /
• pp.812-824
• /
• 2013

Reserpine, an anti-hypertensive drug, is able to positively modulate several phenotypes associated with $A{\beta}$ toxicity in a Caenorhabditis elegans model of Alzheimer's disease (AD). We investigated into the therapeutic effects of reserpine on mammalian neurodegenerative disorders, and found that significant alteration of the key factors influencing AD was detected in Tg2576 mice after reserpine treatment for 30 days. The aggressive behavior of Tg2576 mice was significantly improved upon reserpine treatment, whereas their social contact was consistently maintained. Furthermore, the levels of $A{\beta}$-42 peptide in the hippocampus of the brain and blood serum were lower in the reserpine-treated group than in the vehicle-treated group. Among g-secretase components, the expression levels of PS-2, Pen-2, and APH-1 were slightly lower in reserpine-treated Tg2576 mice, although a significant change in nicastrin (NCT) expression was not detected. Furthermore, the serum level of nerve growth factor (NGF) increased in reserpine-treated Tg2576 mice compared with vehicle-treated mice. Among down-stream effectors of the NGF receptor TrkA signaling pathway, reserpine treatment induced elevation of TrkA phosphorylation and reduction of ERK phosphorylation. In addition, in the NGF receptor $p75^{NTR}$ signaling pathway, the expression levels of $p75^{NTR}$ and Bcl-2 were enhanced in reserpine-treated Tg2576 mice compared with vehicle-treated mice, whereas the expression level of RhoA declined. Overall, these results suggest that reserpine can help relieve AD pathogenesis in Tg2576 mice through downregulation of $A{\beta}$-42 deposition, alteration of ${\gamma}$-secretase components, and regulation of NGF metabolism.

• Asian-Australasian Journal of Animal Sciences
• /
• v.19 no.4
• /
• pp.593-600
• /
• 2006

The effects of breed and sex on individual growth performance and feeding behaviour were studied between 45 and 90 kg BW in two replicates of forty group-housed pigs. The first and the second replicates were carried out during the warm season (i.e. between February and April 2003) and during the hot season (i.e. between August and October 2003), respectively. During the warm season, ambient temperature and relative humidity averaged $25.3^{\circ}C$ and 86.0%. The corresponding values for the hot season were $27.9^{\circ}C$ and 83.6%. The pigs were grouped in pens of 10 animals on the basis of breed (Creole or Large White) and sex (gilt or castrated male) and given ad libitum access to a grower diet (9.0 MJ/kg net energy and 158 g/kg crude protein) via feed intake recording equipment (Acema 48). An ear-tag transponder was inserted into each pig and this allowed the time, duration, and size of individual visits to be recorded. The growth performance and feeding pattern were significantly affected by breed, sex, and season. The Creole pigs (CR) had a lower average daily gain (ADG) (642 vs. 861 g/d, p<0.01) and carcass lean content ($LC_{90kg}$) (35.4 vs. 54.5%; p<0.01) and a higher backfat thickness at 90 kg BW ($BT_{90kg}$) (23.4 vs. 10.4 mm; p<0.01) than Large White pigs (LW) whereas the average daily feed intake (ADFI) was not affected by breed (2.34 vs. 2.22 kg/d, respectively for CR and LW pigs; p>0.10). Consequently, the food:gain ratio was higher in CR than in LW (3.65 vs. 2.58; p<0.01). CR had less frequent meals but ate more feed per meal than LW (5.9 vs. 8.8 meals/d and 431 vs. 279 g/meal; p<0.01). The rate of feed intake was lower (27.6 vs. 33.9 g/min; p<0.01) and the ingestion time per day and per meal were higher in CR than in LW (87.1 vs. 69.7 min/d and 15.8 vs. 8.4 min/meal; p<0.01). The ADFI and BT90 kg were higher (2.38 vs. 2.17 kg/d and 18.1 vs. 15.9 mm; p<0.05) and LC90 kg was lower (43.5 vs. 46.4%; p<0.01) in castrated males (CM) than in gilts (G) whereas ADG was not affected by sex (p = 0.12). The difference in lean content between CM and G was greater in CR than in LW. The ADFI and ADG were reduced during the hot season (2.18 vs.2.38 kg/d and 726 vs. 777 g/d, respectively; p<0.05) whereas feed conversion and carcass lean content were not affected by season (p>0.05). Average feeding time per meal and meal size decreased during the hot season (10.9 vs. 13.2 min/meal and 316 vs. 396 g/meal; p<0.01) whereas the rate of feed intake was not affected by season (p = 0.83). On average, 0.69 of total feed intake was consumed during the diurnal period. However, this partition of feed intake was significantly affected by breed, sex, and season. In conclusion, the breed, sex and season significantly affect performance and feeding pattern in growing pigs raised in a tropical climate. Moreover, the results obtained in the present study suggest that differences observed in BW composition between CR and LW are associated with difference in feeding behaviour, in particular, the short-term regulation of feed intake.

• The Korean Journal of Pharmacology
• /
• v.26 no.2
• /
• pp.193-207
• /
• 1990

Transforming growth factor ${\beta}(TGF-{\beta})$ is a multifunctional polypeptide with diverse effects on the proliferation, differentiation and other functions in many cell types. $TGF-{\beta}$ is highly abundant in bone matrix and induces divergent responses in many aspects of bone cell metabolism . Several lines of investigation indicate that matrix-associated $TGF-{\beta}$ is the products of bone cells themselves. However, exact bone cell type reponsible for the production of $TGF-{\beta}$ is still in controversy, The present study was undertaken to determine the cellular origin of matrix-associated $TGF-{\beta}$ and to assess how different bone cells respond to $TGF-{\beta}$. As a prerequisite for this, 5 bone cell populations of distinct phenotype were isolated from fetal calvaria with sequential enzyme digestion protocol and biochemical characterization. Calvarial cell populations released in early stage showed fibroblastic features whereas populations relesed later was enriched with osteoblast-like cell as judged by their acid and alkaline phosphatase activities, cAMP responsiveness to parathyroid hormone, calcitonin and prostaglandin $E_2$ and collagen synthesis rate. By polyacylamide gel and immunoblot analysis of bone and calvarial cell extracts, presence of $TGF-{\beta}$ in bone tissues and production of $TGF-{\beta}$ by bone cells were confirmed again. Subsequent analysis of calvarial cell extracts prepared as individual population revealed that all calvarial cell populations synthesize $TGF-{\beta}$. Exogenously added $TGF-{\beta}$ induced biphasic response upon bone cell proliferation under serum-free condition. In osteoblastic cell populations, it was stimulatory whereas inhibitory in fibroblastic cell populations. In contrast, collagen and noncollagen protein synthesis of all calvarial cell populations were stimulated by $TGF-{\beta}$. Enhancement of protein synthesis was found to be more general rather than specific for collagen synthesis. In addition, effects of $TGF-{\beta}$ on protein synthesis were independent to its effects on cell proliferation. In summary, production of $TGF-{\beta}$ by bone cells and differential actions on various cell populations observed in this study suggest that $TGF-{\beta}$ may play an important role in the regulation of bone metabolism by modulating the specific cellular functions in autocrine and paracrine fashion.

• Korean Journal of Microbiology
• /
• v.43 no.4
• /
• pp.325-330
• /
• 2007

RNase E is an essential Escherichia coli endoribonuclease that plays a major role in the decay and processing of a large fraction of RNAs in the cell and expression of N-terminal domain consisted of 1-498 amino acids (N-Rne) is sufficient to support normal cellular growth. By utilizing these properties of RNase E, we developed a genetic system to screen for amino acid substitutions in the catalytic domain of the protein (N-Rne) that lead to various phenotypes. Using this system, we identified three kinds of mutants. A mutant N-Rne containing amino acid substitution in the S1 domain (I6T) of the protein was not able to support survival of E. coli cells, and another mutant N-Rne with amino acid substitution at the position 488 (R488C) in the small domain enabled N-Rne to have an elevated ribonucleolytic activity, while amino acid substitution in the DNase I domain (N305D) only enabled N-Rne to support survival of E. roli cells when the mutant N-Rne was over-expressed. Analysis of copy number of ColEl-type plasmid revealed that effects of amino acid substitution on the ability of N-Rne to support cellular growth stemmed from their differential effects on the ribonucleolytic activity of N-Rne in the cell. These results imply that the genetic system developed in this study can be used to isolate mutant RNase E with various phenotypes, which would help to unveil a functional role of each subdomain of the protein in the regulation of RNA stability in E. coli.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
• /
• v.26 no.3
• /
• pp.254-261
• /
• 2000

The present study has attempted to look into the mechanism of ras-induced carcinogenesis in a human epithelial cell system. Human epithelial cells immortalized with Ad12-SV40 hybrid virus were used to assess carcinogenic potential of the ras-oncogene. Cells transfected with pSV2-ras showed characteristics of cellular transformation. The transformation parameters such as cell density, soft-agar colony formation, and cell aggregation were significantly increased in the cells expressing ras oncoprotein. In addition, the duration required for the appearance of foci was shortened in the ras-transfected cells. Consistent with other reports, our results demonstrated an evidence that the ras-oncogene induced the cellular transformation of human epithelial cell system. When a high concentration of glucocorticoid was added into the media, transformation process was accelerated. It is speculated that glucocorticoid may provide an advantageous environment for the proliferation of the transformed cells. The induction of the intracellular free calcium concentrations following agonist treatment was significantly lower in the transformed cells than in the control cells. These effects were more manifested in the presence of extracellular cacium, indicating that the transformation process may alter the influx pathway of extracellular calcium. The induction of $IP_3$ following agonist treatment was also lower in the transformed cells than in the control cells. Thus, it is suggested that phospholipase C-coupled pathway was down-regulated in the process of the ras-induced transformation. While the levels of $TGF-{\beta}_1$ and PAI-2 mRNAs were decreased, the level of fibronectin mRNA was increased. The results indicate that mechanism of the ras-induced transformation may be associated with the altered expressions of growth regulatory factors. The present study demonstrates an evidence that the ras-induced cellular transformation may be associated with alteration of signal transduction and growth regulatory factors. The study will contribute to improve the understanding of molecular mechanism of epithelium-derived cancers including oral cancer.

• Clinical and Experimental Pediatrics
• /
• v.45 no.9
• /
• pp.1106-1113
• /
• 2002

Purpose : Nuclear ($factor-{\kappa}BNF-{\kappa}B$) is now recognized as playing a potential role in programmed cell death and the adaptive response to various stress. Cellular hypoxia is a primary manifestation of many cardiovascular diseases. It seems that vascular endothelial growth factor (VEGF) and insulin like growth factor-I(IGF-I) have a function as a protective molecule in the heart against several stress including hypoxia. In this study, the role of $NF-{\kappa}B$ to the cellular response and regulation of protective molecules against the acute hypoxia in the heart was studied. Methods : To cause acute hypoxic stress to the heart, Sprague Dawley rats were exposed to hypoxic chamer($N_2$ 92% and $O_2$ 8%). After the hypoxic exposure, nuclear proteins, total proteins and mRNA were isolated from heart. Translocation of the transcription factors $NF-{\kappa}B$, NF-ATc, AP-1 and NKX-2.5 were evaluated by electrophoretic mobility shift assay(EMSA). The expression of IGF-I and VEGF were studied before and after the hypoxic stress by competitive-PCR, Northern hybridization and Western hybridization. To confirm the role of the $NF-{\kappa}B$ in the heart, the rats also were pretreated with diethyl-dithiocarbamic acid(DDTC) into peritoneal cavity to block $NF-{\kappa}B$ translocation into nucleus. Results : The expression of $NF-{\kappa}B$, AP-1 and NF-ATc were increased by the hypoxic stress. Increased expression of the VEGF and IGF-I were also observed by the hypoxic stress. However, the blocking of the $NF-{\kappa}B$ translocation reduced those expressions of VEGF and IGF-I. Conclusion : These results suggest that $NF-{\kappa}B$ has a protective role against the acute hypoxia through several gene expression, especially VEGF and IGF-I in heart muscle.