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High susceptibility of metastatic cells derived from human prostate and colon cancer cells to TRAIL and sensitization of TRAIL-insensitive primary cells to TRAIL by 4,5-dimethoxy-2-nitrobenzaldehyde
Hak-Bong Kim, Mi-Ju Kim, Dae-Young Kim, Jae-Won Lee, Jae-Ho Bae, Dong-Wan Kim, Chi-Dug Kang, Sun-Hee Kim
Molecular Cancer , 2011, DOI: 10.1186/1476-4598-10-46
Abstract: PC3-MM2 and KM12L4A cells with high level of c-Myc and DNA-PKcs were more susceptible to TRAIL than their poorly metastatic primary PC3 and KM12 cells, which was associated with down-regulation of c-FLIPL/S and Mcl-1 and up-regulation of the TRAIL receptor DR5 but not DR4 in both metastatic cells. Moreover, high susceptibility of these metastatic cells to TRAIL was resulted from TRAIL-induced potent activation of caspase-8, -9, and -3 in comparison with their primary cells, which led to cleavage and down-regulation of DNA-PKcs. Knockdown of c-Myc gene in TRAIL-treated PC3-MM2 cells prevented the increase of DR5 cell surface expression, caspase activation and DNA-PKcs cleavage and attenuated the apoptotic effects of TRAIL. Moreover, the suppression of DNA-PKcs level with siRNA in the cells induced the up-regulation of DR5 and active caspase-8, -9, and -3. We also found that 4,5-dimethoxy-2-nitrobenzaldehyde (DMNB), a specific inhibitor of DNA-PK, potentiated TRAIL-induced cytotoxicity and apoptosis in relatively TRAIL-insensitive PC3 and KM12 cells and therefore functioned as a TRAIL sensitizer.This study showed the positive relationship between c-Myc expression in highly metastatic human prostate and colon cancer cells and susceptibility to TRAIL-induced apoptosis and therefore indicated that TRAIL might be used as an effective therapeutic modality for advanced metastatic cancers overexpressing c-Myc and combination of TRAIL therapy with agent that inhibits the DNA-PKcs/Akt signaling pathway might be clinically useful for the treatment of relatively TRAIL-insensitive human cancers.Despite the improvement of therapeutic strategies against cancer, the acquisition of invasive/metastatic capabilities and the development of resistance to therapy in cancer cells are still critical problems for successful cancer therapy because recurrent or metastatic cancers that appear after the initial radiotherapy or chemotherapy are generally refractory to secondary therapies [1]. Som
TRAIL sensitize MDR cells to MDR-related drugs by down-regulation of P-glycoprotein through inhibition of DNA-PKcs/Akt/GSK-3β pathway and activation of caspases
Suk-Bin Seo, Jung-Gu Hur, Mi-Ju Kim, Jae-Won Lee, Hak-Bong Kim, Jae-Ho Bae, Dong-Wan Kim, Chi-Dug Kang, Sun-Hee Kim
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-199
Abstract: MDR variants, CEM/VLB10-2, CEM/VLB55-8 and CEM/VLB100 cells, with gradually increased levels of P-gp derived from human lymphoblastic leukemia CEM cells, were gradually more susceptible to TRAIL-induced apoptosis and cytotoxicity than parental CEM cells. The P-gp level of MDR variants was positively correlated with the levels of DNA-PKcs, pAkt, pGSK-3β and c-Myc as well as DR5 and negatively correlated with the level of c-FLIPs. Hypersensitivity of CEM/VLB100 cells to TRAIL was accompanied by the activation of mitochondrial apoptotic pathway as well as the activation of initiator caspases. In addition, TRAIL-induced down-regulation of DNA-PKcs/Akt/GSK-3β pathway and c-FLIP and up-regulation of cell surface expression of death receptors were associated with the increased susceptibility to TRAIL of MDR cells. Moreover, TRAIL inhibited P-gp efflux function via caspase-3-dependent degradation of P-gp as well as DNA-PKcs and subsequently sensitized MDR cells to MDR-related drugs such as vinblastine and doxorubicin. We also found that suppression of DNA-PKcs by siRNA enhanced the susceptibility of MDR cells to vincristine as well as TRAIL via down-regulation of c-FLIP and P-gp expression and up-regulation of DR5.This study showed for the first time that the MDR variant of CEM cells was hypersensitive to TRAIL due to up-regulation of DR5 and concomitant down-regulation of c-FLIP, and degradation of P-gp and DNA-PKcs by activation of caspase-3 might be important determinants of TRAIL-induced sensitization of MDR cells to MDR-related drugs. Therefore, combination of TRAIL and chemotherapeutic drugs may be a good strategy for treatment of cancer with multidrug resistance.Acquired resistance to chemotherapeutic agents remains a major obstacle for the effective treatment of many advanced and metastatic cancers. Several mechanisms are thought to be involved in the development of multidrug resistance (MDR), defined by simultaneous cross-resistance to a variety of anticancer drugs
Comparison of Perinatal Outcomes in Late Preterm Spontaneous and Indicated Preterm Birth Neonates  [PDF]
Dasom Chun, Eun Hye Yoo, Ji Young Lee, Hyun Mi Kim, Mi Ju Kim, Won Joon Seong, Hyun-Hwa Cha
Open Journal of Obstetrics and Gynecology (OJOG) , 2016, DOI: 10.4236/ojog.2016.612083
Abstract: Objective: We aimed to compare the perinatal outcomes in late preterm spontaneous and indicated birth neonates. Methods: We studied 289 late preterm births, classified as either aspontaneous late preterm birth (sLPTB) group (preterm labor with intact membranes and preterm premature rupture of membranes) or an indicated late preterm birth (iLPTB) group (hypertensive disorder in pregnancy, placental causes, and maternal diseases), according to the delivery indication. We then compared the maternal and neonatal characteristics and perinatal outcomes, including the Apgar score, admission to the neonatal intensive care unit (NICU) or special care nursery (SCN), duration of NICU stay, and the rate of composite morbidity (antibiotic use, hypoglycemia, hypocalcemia, hyperbilirubinemia requiring phototherapy, respiratory support, and respiratory distress syndrome). Results: A total of 198 neonates were in the sLPTB group and 91 were in the iLPTB group. In spite of greater gestational age at the time of delivery in the iLPTB group, the mean birth weight was lower than that in the sLPTB group. Additionally, the iLPTB group showed lower Apgar scores, and higher rates of NICU or SCN admission, respiratory support, and hypoglycemia, but there was no difference in the rate of composite morbidity between the two groups. Conclusion: iLPTB neonates had lower birth weights despite greater gestational age than those in the sLPTB group, but there was no difference in the rate of composite morbidity between the two groups.
A New Predictive Index for Osteoporosis in Men under 70 Years of Age: An Index to Identify Male Candidates for Osteoporosis Screening by Bone Mineral Density
Lee Oh Kim,Hyeon-Ju Kim,Mi Hee Kong
Journal of Osteoporosis , 2014, DOI: 10.1155/2014/781897
Abstract: Background. Bone mineral density (BMD) screening guidelines for osteoporosis in men seem to have remained unclear. We aimed to set up a predictive index for the osteoporosis(PIO) in men under 70 years of age and present the optimal cutoff value of it, so that clinicians might use it to identify male candidates who benefit from taking the BMD screening. Methods. Adult men under 70 years old who met certain criteria were included. With the determined significant predictors for osteoporosis, we created a new index that presumably best predicts the osteoporosis and compared the predictability of it to other variables. Lastly, the optimal cutoff value of the PIO was calculated. Results. A total of 359 men were included. Age, weight, and current smoking status turned out to be significant predictors for osteoporosis. The PIO was as follows: [age(years) + 10 (for current smoker)]/weight(kg). Compared to other variables, the PIO showed the greatest predictive performance with the optimal cutoff point being 0.87 at which sensitivity and specificity were 71.9% and 70.0%, respectively. Conclusion. A new predictive index appeared to predict the presence of osteoporosis fairly well and thus can be used with its cutoff point to identify men under 70 years of age who need BMD screening. 1. Introduction Male osteoporosis has been increasingly recognized as a major global health problem over the last decade. Demographically, its incidence is increasing and expected to keep rising given prolonged life span. Specifically, the prevalence of osteoporosis in Korean men aged 50 years or older was 7.5% according to national health survey data [1]. This figure was higher than that of Caucasians and the increasing trends for osteoporosis seemed to have been on steady rise since early twenty-first century. The clinical importance of osteoporosis comes from the fact that fractures associated with osteoporosis show high morbidity and mortality in men compared with women [2]. In this regard, early detection of men with osteoporosis is determined by bone mineral density (BMD), so that they may benefit from early treatment that seems important strategy. Currently, BMD is still considered a single important predictor of fracture risk [3–5] despite a wide use of FRAX, a powerful tool to predict 10-year fracture probability that also includes BMD as one of data to calculate the risk [6]. In this sense, there is no doubt that BMD measurement has significant screening value and now the point is how to identify men who are likely to have osteoporosis and should, therefore, undergo BMD
Prevalence and Predictors of Polypharmacy among Korean Elderly
Hong-Ah Kim, Ju-Young Shin, Mi-Hee Kim, Byung-Joo Park
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098043
Abstract: Objective Polypharmacy is widespread in the elderly because of their multiple chronic health problems. The objective of this study was to investigate the prevalence and predictors associated with polypharmacy in a nationally representative sample of Korean elderly individuals. Methods We used the Korea Health Insurance Review and Assessment Service – National Patient Sample (HIRA-NPS) data from 2010 and 2011. We used information on 319,185 elderly patients (aged 65 years or older) between January 1, 2010 and December 31, 2011 from the HIRA-NPS database. We defined ‘polypharmacy’ as the concurrent use of 6 medications or more per person, ‘major polypharmacy’ as 11 medications or more, and ‘excessive polypharmacy’ as 21 medications or more. The frequency and proportion (%) and their 95% confidence intervals were presented according to the polypharmacy definition. Polypharmacy was visualized by the Quantum Geographic Information Systems (QGIS) program to describe regional differences in patterns of drug use. Multivariate ordinal logistic regression was performed to estimate odds ratios (ORs) and their 95% confidence intervals (CI) to investigate the risk factors for polypharmacy. Results Of the Korean elderly studied, 86.4% had polypharmacy, 44.9% had major polypharmacy and 3.0% had excessive polypharmacy. Polypharmacy was found to be primarily concentrated in the Southwest region of the country. Significant associations between polypharmacy and the lower-income Medical Aid population (OR = 1.52, 95% CI 1.47, 1.56) compared with National Health Insurance patients was observed. Conclusions Nationwide efforts are needed for managing polypharmacy among Korean elderly patients. In particular, a national campaign and education to promote appropriate use of medicines for the Medical Aid population is needed.
Photofunctional Co-Cr Alloy Generating Reactive Oxygen Species for Photodynamic Applications
Kang-Kyun Wang,Bong-Jin Kim,Mi Hee Lee,Byeong-Ju Kwon
International Journal of Photoenergy , 2013, DOI: 10.1155/2013/618062
Preparation and Characterization of Self-Emulsified Docetaxel
Gyeong Hae Kim,Ju Young Lee,Yun Mi Kang,Kkot Nim Kang,E. Sle Kim,Da Yeon Kim,Jae Ho Kim,Moon Suk Kim
Journal of Nanomaterials , 2011, DOI: 10.1155/2011/860376
Abstract: The aim of this paper was to prepare a self-microemulsifying docetaxel (Dtx) using PLGA, Tetraglycol, Labrasol, and Cremophor ELP. The prepared Dtx-loaded self-microemulsifying system (SMES) showed the initial size of the range of 80–100 nm with narrow size distribution and the negative zeta-potential values. Its morphology was a spherical shape by atomic force microscopy. In experiment of stability, Dtx-loaded SMES prepared in DW and BSA condition showed good stability at 37°C for 7 days. The viability of the B16F10 cells incubated with Dtx-loaded SMES, Dtx-solution, and Taxol were decreased as a function of incubation time. In conclusion, we confirmed that Dtx-loaded SMES showed an inhibitory effect for proliferation of B16F10 melanoma cells.
Hyaluronan- and RNA-binding deubiquitinating enzymes of USP17 family members associated with cell viability
Ju-Mi Shin, Kyong-Jai Yoo, Myung-Sun Kim, Dongku Kim, Kwang-Hyun Baek
BMC Genomics , 2006, DOI: 10.1186/1471-2164-7-292
Abstract: While identifying putative ubiquitin specific protease (USP) enzymes that contain a conserved Asp (I) domain in humans, 4 USP17 subfamily members, highly homologous to DUB-3, have been found (USP17K, USP17L, USP17M, and USP17N), from human chorionic villi. Expression analysis showed that USP17 transcripts are highly expressed in the heart, liver, and pancreas and are expressed moderately in various human cancerous cell lines. Amino acid sequence analysis revealed that they contain the highly conserved Cys, His, and Asp domains which are responsible for the deubiquitinating activity. Biochemical enzyme assays indicated that they have deubiquitinating activity. Interestingly, the sequence analysis showed that these proteins, with exception of USP17N, contain the putative hyaluronan/RNA binding motifs, and cetylpyridinium chloride (CPC)-precipitation analysis confirmed the association between these proteins and intracellular hyaluronan and RNA.Here, we report that the overexpression of these proteins, with exception of USP17N, leads to apoptosis, suggesting that the hyaluronan and RNA binding motifs in these enzymes play an important role in regulating signal transduction involved in cell death.The post-translational modification by ubiquitin (Ub) plays an essential role for numerous cellular functions such as protein degradation, cell cycle control, transcriptional regulation, immune response, apoptosis, oncogenesis, pre-implantation, and intracellular signaling pathways [1-6]. Conjugation of ubiquitin to a target protein is achieved by the sequential enzymatic actions via ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3). A novel ubiquitination factor (E4) required for efficient multiubiquitination has been identified in yeast [7]. Proteins modified with a polyubiquitin chain are then unfolded and degraded by the 26S proteasome [1,4,5]. Deubiquitination, a removal of ubiquitin from ubiquitin-conjugated protein substrate
IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-κB- and PI3-kinase/Akt-dependent pathways
Sue-Yun Hwang, Ju-Young Kim, Kyoung-Woon Kim, Mi-Kyung Park, Youngmee Moon, Wan-Uk Kim, Ho-Youn Kim
Arthritis Research & Therapy , 2004, DOI: 10.1186/ar1038
Abstract: Increasing attention is being given to the role of IL-17, a proinflammatory cytokine produced by activated T cells, in the perpetuation of joint inflammation in rheumatoid arthritis (RA) [1-3]. Overproduction of this cytokine has been associated with elevated production of proinflammatory mediators such as IL-6, IL-8, granulocyte/macrophage-colony-stimulating factor, GRO-α, and prostaglandin E2 in various cell types [4,5]. Of these targets, IL-6 and IL-8 are most likely to act as major instigators of RA joint inflammation, since disruption of their functions either by gene knockout [6] or by systemic IL-4 treatment [7] leads to protection against arthritis in animal models. Early studies have also denominated IL-1β and tumor necrosis factor α (TNF-α) as major inducers of IL-6 and IL-8 in RA synovium, and IL-17 appears to exert an additive and synergistic effect with these two cytokines [5]. However, results from studies using mice and human joint explants suggest that IL-17 is capable of provoking inflammatory responses by itself [8,9]. Yet by comparison with the vast information about the role of IL-1β and TNF-α in synovial inflammation, relatively little is known about the mode of IL-17-mediated activation.The cytoplasmic tail of IL-17R (IL-17 receptor) does not contain any known motifs associated with intracellular signaling, and not much is known about the pathway that relays IL-17-mediated stimulation on to the induction of target cytokines. The involvement of JAK/STAT (Janus kinase/signal transducer and activator of transcription) and TRAF6 (TNF-receptor-associated factor 6) has been suggested to transmit IL-17 signaling in human monocyte cell line [10] and embryonic fibroblasts [11], respectively, and yet cytoplasmic players transmitting IL-17-mediated activation in RA synovial fibroblasts remain to be investigated. Moreover, recent searches using the characteristic 'four-cysteine motif' of IL-17 identified a panoply of IL-17 family members, listed as IL-17B
Association of Low Muscle Mass and Combined Low Muscle Mass and Visceral Obesity with Low Cardiorespiratory Fitness
Tae Nyun Kim, Man Sik Park, You Jeong Kim, Eun Ju Lee, Mi-Kyung Kim, Jung Min Kim, Kyung Soo Ko, Byoung Doo Rhee, Jong Chul Won
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0100118
Abstract: Objective Previous studies have shown that low cardiorespiratory fitness (CRF), visceral obesity and low muscle mass may share pathophysiological mechanisms, such as insulin resistance and chronic inflammation. In this study, we investigated whether low CRF is associated with low muscle mass, visceral obesity, and visceral obesity combined with low muscle mass. Research Design and Methods The associations between CRF and low muscle mass and combined low muscle mass and visceral obesity were examined in 298 apparently healthy adults aged 20–70 years. Low muscle mass was defined using a skeletal muscle mass index (SMI) that was calculated using dual energy X-ray absorptiometry. Visceral obesity was defined as a visceral fat area (VFA) exceeding 100 cm2 in women and 130 cm2 in men. We classified the participants into 4 low muscle mass/visceral obesity groups according to SMI and VFA. CRF was measured using a cycle ergometer test. Results CRF level correlated positively with SMI and negatively with VFA. Individuals with low muscle mass had lower CRF values than those without low muscle mass. After adjustment for age, sex, lifestyle factors, and markers for insulin resistance and inflammation, participants in the lowest quartile of CRF had an odds ratio (OR) for low muscle mass of 4.98 compared with those in the highest quartile (95% confidence interval (CI) = 1.19–12.99; P for trend = 0.001) and an OR for combined low muscle mass and visceral obesity of 31.46 (95% CI = 4.31–229.68; P for trend = 0.001). Conclusions Individuals with lower CRF exhibited increased risk of low muscle mass and combined low muscle mass and visceral obesity. These results suggest that low CRF may be a potential indicator for low muscle mass and combined low muscle mass and visceral obesity in Korean adults.
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