Publications by authors named "Sarah Yoon"

33 Publications

TPRG1-AS1 induces RBM24 expression and inhibits liver cancer progression by sponging miR-4691-5p and miR-3659.

Liver Int 2021 Jul 30. Epub 2021 Jul 30.

Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.

Background & Aims: Noncoding RNAs (ncRNAs) play critical roles in hepatocellular carcinoma (HCC) progression. Here, by performing RNA-sequencing (RNA-Seq) profiling, we sought to identify novel ncRNAs that potentially drive the heterogeneous progression of liver cancers.

Methods: RNA-Seq profiles were obtained from 68 HCC specimens and 10 samples of adjacent non-tumour liver tissues. The functional significance of the potential driver ncRNAs was evaluated by cell experiments.

Results: TPRG1-AS1 was identified as a potential driver noncoding RNA that promotes heterogeneous liver cancer progression. TPRG1-AS1 induced tumour suppressor RNA-binding motif protein 24 (RBM24), suppressing tumour growth by activating apoptotic tumour cell death. In addition, we report that TPRG1-AS1 acts as a competing endogenous RNA (ceRNA) for RBM24, sponging miR-4691-5p and miR-3659 to interfere with their binding to RBM24.

Conclusions: We suggest that TPRG1-AS1 is a novel ceRNA sponging miR-4691-5p and miR-3659, resulting in RBM24 expression and suppression of liver cancer growth. Our results provide new insights into the functions of ncRNAs in heterogeneous HCC progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/liv.15026DOI Listing
July 2021

Endoplasmic Reticulum Stress Induces CAP2 Expression Promoting Epithelial-Mesenchymal Transition in Liver Cancer Cells.

Mol Cells 2021 Aug;44(8):569-579

Department of Physiology, Ajou University School of Medicine, Suwon 16499, Korea.

() has been addressed as a candidate biomarker in various cancer types. Previously, we have shown that is expressed during multi-step hepatocarcinogenesis; however, its underlying mechanisms in liver cancer cells are not fully elucidated yet. Here, we demonstrated that endoplasmic reticulum (ER) stress induced expression, and which promoted migration and invasion of liver cancer cells. We also found that the ER stress-induced CAP2 expression is mediated through activation of protein kinase C epsilon (PKCε) and the promotor binding of activating transcription factor 2 (ATF2). In addition, we further demonstrated that expression promoted epithelial-mesenchymal transition (EMT) through activation of Rac1 and ERK. In conclusion, we suggest that ER stress induces expression promoting EMT in liver cancers cells. Our results shed light on the novel functions of in the metastatic process of liver cancer cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14348/molcells.2021.0031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424138PMC
August 2021

USO1 isoforms differentially promote liver cancer progression by dysregulating the ER-Golgi network.

Carcinogenesis 2021 Jul 22. Epub 2021 Jul 22.

Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.

Alternative splicing of RNA transcripts plays an important role in cancer development and progression. Recent advances in RNA-seq technology have made it possible to identify alternately spliced events in various types of cancer; however, research on hepatocellular carcinoma (HCC) is still limited. Here, by performing RNA-Seq profiling of HCC transcripts at isoform level, we identified tumor-specific and molecular subtype-dependent expression of the USO1 isoforms, which we designated as a normal form USO1-N (XM_001290049) and a tumor form USO1-T (NM_003715). The expression of USO1-T, but not USO1-N, was associated with worse prognostic outcomes of HCC patients. We confirmed that the expression of USO1-T promoted an aggressive phenotype of HCC, both in vitro and in vivo. In addition, structural modeling analyses revealed that USO1-T lacks an ARM10 loop encoded by exon 15, which may weaken the dimerization of USO1 and its tethering to GM130. We demonstrated that USO1-T ensured unstacking of the Golgi and accelerated the trafficking from ER to Golgi and plasma membrane in multiple liver cancer cells. ERK and GRASP65 were found to be involved in the USO1-T mediated Golgi dysfunction. Conclusively, we provide new mechanophysical insights into the USO1 isoforms that differentially regulate the ER-Golgi network, promoting the heterogeneous HCC progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/carcin/bgab067DOI Listing
July 2021

YAP inactivation in estrogen receptor alpha-positive hepatocellular carcinoma with less aggressive behavior.

Exp Mol Med 2021 Jun 18;53(6):1055-1067. Epub 2021 Jun 18.

Department of Pathology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea.

The expression of estrogen receptor alpha (ERα, encoded by ESR1) has been shown to be associated with the prognostic outcomes of patients in various cancers; however, its prognostic and mechanistic significance in hepatocellular carcinoma (HCC) remain unclear. Here, we evaluated the expression of ERα and its association with clinicopathological features in 339 HCC patients. ERα was expressed in 9.4% (32/339) of HCCs and was related to better overall survival (OS; hazard ratio [HR] = 0.11, p = 0.009, 95% C.I. = 0.016-0.82) and disease-free survival (DFS, HR = 0.4, p = 0.013, 95% C.I. = 0.18-0.85). ERα expression was also associated with features related to more favorable prognosis, such as older age, lower serum alpha-fetoprotein level, and less microvascular invasion (p < 0.05). In addition, to obtain mechanistic insights into the role of ERα in HCC progression, we performed integrative transcriptome data analyses, which revealed that yes-associated protein (YAP) pathway was significantly suppressed in ESR1-expressing HCCs. By performing cell culture experiments, we validated that ERα expression enhanced YAP phosphorylation, attenuating its nuclear translocation, which in turn suppressed the downstream signaling pathways and cancer cell growth. In conclusion, we suggest that ERα expression is an indicator of more favorable prognosis in HCC and that this effect is mediated by inactivation of YAP signaling. Our results provide new clinical and pathobiological insights into ERα and YAP signaling in HCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s12276-021-00639-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257598PMC
June 2021

"ACEing" the Evidence Within Physical Medicine and Rehabilitation (PM&R).

MedEdPORTAL 2020 12 11;16:11051. Epub 2020 Dec 11.

Professor, Department of Medicine, Loma Linda University School of Medicine; Professor, Medical Education, Loma Linda University School of Medicine; Associate Dean for Educational Quality and Outcomes, Loma Linda University School of Medicine.

Introduction: While evidence-based medicine (EBM) is important in all fields of medicine, it can be specifically challenging for the field of physical medicine and rehabilitation (PM&R), a rapidly developing field where the standard hierarchy of evidence does not always apply and randomized controlled trials can be difficult to design. We developed an EBM curriculum for residents that improved EBM competency and was specific to the field of PM&R.

Methods: We developed a blended learning longitudinal approach to EBM designed specifically for PM&R residents, with a pre- and postcourse assessment by the Evidence-Based Practice Questionnaire (EBPQ) and Assessing Competency in EBM (ACE) tool. Interactive presentations paired with structured presession assignments were held for five introductory sessions, followed by monthly EBM and journal club sessions over 1 academic year.

Results: Fourteen residents of varying postgraduate years of training participated in the EBM curriculum from 2018 to 2019. EBPQ scores after completion of 1 academic year of this EBM curriculum were significantly improved compared to precurriculum EBPQ scores. Comparison of pre- and post-EBPQ and ACE tool scores stratified by postgraduate year did not show a significant correlation between resident levels and self-reported prior EBM education.

Discussion: This longitudinal blended learning EBM curriculum resulted in an increase in residents' self-reported behaviors and knowledge/skills regarding EBM. The curriculum was also effective in advancing competency of the residents to an EBM Advanced level using the ACE tool. The curriculum can be easily replicated in other PM&R residency programs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15766/mep_2374-8265.11051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732134PMC
December 2020

Dynamics of Genomic, Epigenomic, and Transcriptomic Aberrations during Stepwise Hepatocarcinogenesis.

Cancer Res 2019 Nov 10;79(21):5500-5512. Epub 2019 Sep 10.

Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.

Hepatocellular carcinoma (HCC) undergoes a stepwise progression from liver cirrhosis to low-grade dysplastic nodule (LGDN), high-grade dysplastic nodule (HGDN), early HCC (eHCC), and progressed HCC (pHCC). Here, we profiled multilayered genomic, epigenomic, and transcriptomic aberrations in the stepwise hepatocarcinogenesis. Initial DNA methylation was observed in eHCC (e.g., , and ) while more extensive methylation was observed in pHCC. In addition, eHCCs showed an initial loss of DNA copy numbers of tumor suppressor genes in the 4q and 13q regions, thereby conferring survival benefits to cancer cells. Transcriptome analysis revealed that HGDNs expressed endoplasmic reticulum (ER) stress-related genes, while eHCC started to express oncogenes. Furthermore, integrative analysis indicated that expression of the serine peptidase inhibitor, Kazal type 1 (SPINK1), played a pivotal role in eHCC development. Significant demethylation of SPINK1 was observed in eHCC compared to HGDN. The study also demonstrated that ER stress may induce SPINK1 demethylation and expression in liver cancer cells. In conclusion, these results reveal the dynamics of multiomic aberrations during malignant conversion of liver cancer, thus providing novel pathobiological insights into hepatocarcinogenesis. SIGNIFICANCE: Multiomics profiling and integrative analyses of stepwise hepatocarcinogenesis reveal novel mechanistic and clinical insights into hepatocarcinogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-19-0991DOI Listing
November 2019

Comparative Effectiveness and Safety of Direct Oral Anticoagulants in Patients with Atrial Fibrillation: A Systematic Review and Meta-Analysis of Observational Studies.

Drug Saf 2019 10;42(10):1135-1148

Centre for Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Cote Ste-Catherine, Suite H410.1, Montreal, QC, H3T 1E2, Canada.

Background: There are no head-to-head randomized controlled trials comparing different direct oral anticoagulants (DOACs). Thus, we systematically reviewed and meta-analyzed observational studies assessing the comparative effectiveness and safety of DOACs for stroke prevention in patients with atrial fibrillation (AF).

Methods: We systematically searched MEDLINE and EMBASE up to February 2019 for observational studies comparing different DOACs head-to-head in patients with AF. Two independent reviewers identified studies, extracted data, and assessed the risk of bias using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool. Random-effects models were used to meta-analyze data across higher-quality studies.

Results: We identified 25 cohort studies including 1,079,565 patients with AF treated with DOACs. Meta-analysis of the 19 studies at moderate risk of bias yielded a similar risk of ischemic stroke for rivaroxaban versus dabigatran (six studies; hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.83-1.04; I: 0%), apixaban versus dabigatran (five studies; HR 0.94; 95% CI 0.82-1.09; I: 0%), and apixaban versus rivaroxaban (four studies; HR 1.07; 95% CI 0.93-1.23; I: 0%). Regarding major bleeding, there was an increased risk for rivaroxaban versus dabigatran (six studies; HR 1.33; 95% CI 1.20-1.47; I: 22%) and decreased risks for apixaban versus either dabigatran (eight studies; HR 0.71; 95% CI 0.64-0.78; I: 0%) or rivaroxaban (eight studies; HR 0.56; 95% CI 0.48-0.65; I: 69%).

Conclusions: As head-to-head trials comparing different DOACs do not exist, available evidence derives exclusively from observational studies. These data suggest that while dabigatran, rivaroxaban, and apixaban have a similar effect on the risk of ischemic stroke, apixaban may be associated with a decreased risk of major bleeding compared with either dabigatran or rivaroxaban.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40264-019-00842-1DOI Listing
October 2019

EPHB6 mutation induces cell adhesion-mediated paclitaxel resistance via EPHA2 and CDH11 expression.

Exp Mol Med 2019 06 3;51(6):1-12. Epub 2019 Jun 3.

Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.

Mutations affect gene functions related to cancer behavior, including cell growth, metastasis, and drug responses. Genome-wide profiling of cancer mutations and drug responses has identified actionable targets that can be utilized for the management of cancer patients. Here, the recapitulation of pharmacogenomic data revealed that the mutation of EPHB6 is associated with paclitaxel resistance in cancer cells. Experimental data confirmed that the EPHB6 mutation induces paclitaxel resistance in various cancer types, including lung, skin, and liver cancers. EPHB6 mutation-induced paclitaxel resistance was mediated by an interaction with EPHA2, which promotes c-Jun N-terminal kinase (JNK)-mediated cadherin 11 (CDH11) expression. We demonstrated that EPHB6-mutated cells acquire cell adhesion-mediated drug resistance (CAM-DR) in association with CDH11 expression and RhoA/focal adhesion kinase (FAK) activation. Targeted inhibition of EPHA2 or CDH11 reversed the acquired paclitaxel resistance, suggesting its potential clinical utility. The present results suggest that the EPHB6 mutation and its downstream EPHA2/JNK/CDH11/RhoA/FAK signaling axis are novel diagnostic and therapeutic targets for overcoming paclitaxel resistance in cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s12276-019-0261-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547695PMC
June 2019

Cardiovascular Disease-Related Morbidity and Mortality in Women With a History of Pregnancy Complications.

Circulation 2019 02;139(8):1069-1079

Department of Epidemiology, Biostatisticcs and Occupational Health, McGill University, Montreal, QC, Canada (S.G., K.F., S.Y., H.A., C.D., R.P.).

Background: Women with a history of certain pregnancy complications are at higher risk for cardiovascular (CVD) disease. However, most clinical guidelines only recommend postpartum follow-up of those with a history of preeclampsia, gestational diabetes mellitus, or preterm birth. This systematic review was undertaken to determine if there is an association between a broader array of pregnancy complications and the future risk of CVD.

Methods: We systematically searched PubMed, MEDLINE and EMBASE (via Ovid), CINAHL, and the Cochrane Library from inception to September 22, 2017, for observational studies of the association between the hypertensive disorders of pregnancy, placental abruption, preterm birth, gestational diabetes mellitus, low birth weight, small-for-gestational-age birth, stillbirth, and miscarriage and subsequent CVD. Likelihood ratio meta-analyses were performed to generate pooled odds ratios (OR) and 95% intrinsic confidence intervals (ICI).

Results: Our systematic review included 84 studies (28 993 438 patients). Sample sizes varied from 250 to 2 000 000, with a median follow-up of 7.5 years postpartum. The risk of CVD was highest in women with gestational hypertension (OR 1.7; 95% ICI, 1.3-2.2), preeclampsia (OR 2.7; 95% ICI, 2.5-3.0), placental abruption (OR 1.8; 95% ICI, 1.4-2.3), preterm birth (OR 1.6; 95% ICI, 1.4-1.9), gestational diabetes mellitus (OR 1.7; 95% ICI, 1.1-2.5), and stillbirth (OR 1.5; 95% ICI, 1.1-2.1). A consistent trend was seen for low birth weight and small-for-gestational-age birth weight but not for miscarriage.

Conclusions: Women with a broader array of pregnancy complications, including placental abruption and stillbirth, are at increased risk of future CVD. The findings support the need for assessment and risk factor management beyond the postpartum period.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.118.036748DOI Listing
February 2019

Recapitulation of pharmacogenomic data reveals that invalidation of SULF2 enhance sorafenib susceptibility in liver cancer.

Oncogene 2018 08 3;37(32):4443-4454. Epub 2018 May 3.

Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.

Gene mutations play critical roles during cancer development and progression, and therefore represent targets for precision medicine. Here we recapitulated the pharmacogenomic data to delineate novel candidates for actionable mutations and therapeutic target drugs. As a proof-of-concept, we demonstrated that the loss-of-function of SULF2 by mutation (N491K) or inhibition enhanced sorafenib sensitivity in liver cancer cells and in vivo mouse models. This effect was mediated by deregulation of EGFR signaling and downstream expression of LCN2. We also report that the liver cancer patients non-responding to sorafenib treatment exhibit higher expression of SULF2 and LCN2. In conclusion, we suggest that SULF2 plays a key role in sorafenib susceptibility and resistance in liver cancer via deregulation of LCN2. Diagnostic or therapeutic targeting of SULF2 (e.g., OKN-007) and/or LCN2 can be a novel precision strategy for sorafenib treatment in cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-018-0291-3DOI Listing
August 2018

Integrative analysis of genomic and epigenomic regulation of the transcriptome in liver cancer.

Nat Commun 2017 10 10;8(1):839. Epub 2017 Oct 10.

Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, 110-744, Republic of Korea.

Hepatocellular carcinoma harbors numerous genomic and epigenomic aberrations of DNA copy numbers and DNA methylation. Transcriptomic deregulation by these aberrations plays key driver roles in heterogeneous progression of cancers. Here, we profile DNA copy numbers, DNA methylation, and messenger RNA expression levels from 64 cases of hepatocellular carcinoma specimens. We find that the frequencies of the aberrancies of the DNA copy-number-correlated (CNVcor) expression genes and the methylation-correlated expression (METcor) genes are co-regulated significantly. Multi-omics integration of the CNVcor and METcor genes reveal three prognostic subtypes of hepatocellular carcinoma, which can be validated by an independent data. The most aggressive subtype expressing stemness genes has frequent BAP1 mutations, implying its pivotal role in the aggressive tumor progression. In conclusion, our integrative analysis of genomic and epigenomic regulation provides new insights on the multi-layered pathobiology of hepatocellular carcinoma, which might be helpful in developing precision management for hepatocellular carcinoma patients.Hepatocellular carcinoma is known to harbour numerous genomic and epigenomic aberrations, driving transcriptomic deregulation. Here, the authors integrate genomic, epigenomic, and expression data to reveal three prognostic subtypes, providing insight to the pathobiology of hepatocellular carcinoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-017-00991-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635060PMC
October 2017

Activated Rac1 regulates the degradation of IκBα and the nuclear translocation of STAT3-NFκB complexes in starved cancer cells.

Exp Mol Med 2016 May 6;48:e231. Epub 2016 May 6.

Department of Physiology, Ajou University School of Medicine, Worldcup-ro, Yeongtong-gu, Gyeonggi-do, Korea.

In several human tumors, signal transducer and activator of transcription 3 (STAT3) and nuclear factor κB (NFκB) are activated and interact; how these STAT3-NFκB complexes are transported to the nucleus is not fully understood. In this study, we found that Rac1 was activated in starved cancer cells and that activated Rac1 coexisted with STAT3 and NFκB. Rac1 knockdown and overexpression of the dominant-negative mutant Rac1N19 inhibited the degradation of IκBα, an inhibitor of NFκB. MG132, an inhibitor of the ubiquitin proteasome pathway, increased the amount of non-phosphorylated IκBα, but not serine-phosphorylated IκBα, indicating that IκBα degradation by Rac1 in starved cancer cells is independent of IκBα serine phosphorylation by IKK. Rac1 knockdown also inhibited the nuclear translocation of STAT3-NFκB complexes, indicating that this translocation requires activated Rac1. We also demonstrated that the mutant STAT3 Y705F could form complexes with NFκB, and these unphosphorylated STAT3-NFκB complexes translocated into the nucleus and upregulated the activity of NFκB in starved cancer cells, suggesting that phosphorylation of STAT3 is not essential for its translocation. To our knowledge, this is the first study demonstrating the crucial role of Rac1 in the function of STAT3-NFκB complexes in starved cancer cells and implies that targeting Rac1 may have future therapeutic significance in cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/emm.2016.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910147PMC
May 2016

Tumor suppressive effect of PARP1 and FOXO3A in gastric cancers and its clinical implications.

Oncotarget 2015 Dec;6(42):44819-31

Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.

Poly (ADP-ribose) polymerase1 (PARP1) has been reported as a possible target for chemotherapy in many cancer types. However, its action mechanisms and clinical implications for gastric cancer survival are not yet fully understood. Here, we investigated the effect of PARP1 inhibition in the growth of gastric cancer cells. PARP1 inhibition by Olaparib or PARP1 siRNA could significantly attenuate growth and colony formation of gastric cancer cells, and which were mediated through induction of G2/M cell cycle arrest but not apoptosis. FOXO3A expression was induced by PARP1 inhibition, suggesting that FOXO3A might be one of downstream target of the PARP1 effect on gastric cancer cell growth. In addition, by performing tissue microarrays on the 166 cases of gastric cancer patients, we could observe that the expression status of PARP1 and FOXO3A were significantly associated with overall survival (OS) and relapse-free survival (RFS). Strikingly, combined expression status of PARP1 and FOXO3A showed better prediction for patient's clinical outcomes. The patient group with PARP1+/FOXO3A- expression had the worst prognosis while the patient group with PARP1-/FOXO3A+ had the most favorable prognosis (OS: P = 6.0 × 10(-9), RFS: P = 2.2 × 10(-8)). In conclusion, we suggest that PARP1 and FOXO3A play critical roles in gastric cancer progression, and might have therapeutic and/or diagnostic potential in clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.6264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792594PMC
December 2015

Comparison of craniofacial growth of untreated Class I and Class II girls from ages 9 to 18 years: a longitudinal study.

Am J Orthod Dentofacial Orthop 2015 Feb;147(2):190-6

Chauncey M. F. Egel Endowed Chair and associate professor, Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pa. Electronic address:

Introduction: The purposes of this study were to examine and compare the craniofacial growth in girls with Class I or Class II occlusion from the ages of 9 to 18.

Methods: Twenty-five Class I (ANB, 1°-4°) and 21 Class II (ANB, >4°) untreated Caucasian girls were selected from the Burlington Growth Centre in Toronto, Ontario, Canada. Cephalograms of each subject at ages 9, 14, and 18 years were traced, and 29 parameters were measured. The growth changes in each parameter from ages 9 to 14, 14 to 18, and 9 to 18 were calculated, and comparisons of each parameter were made between the 2 groups.

Results: From ages 9 to 14, the Class I and Class II groups had similar skeletal growth patterns (increases of SNA and SNB angles, decreases of ANB, MP-SN, and gonial angles). Dentally, the Class II group showed less maxillary incisal proclination and more overbite than did the Class I group. From ages 14 to 18, the 2 groups also showed similar growth patterns, with little sagittal but continued vertical growth, and the MP-SN angle continued to decrease. From ages 9 to 18 (combined periods of 9-14 and 14-18), the 2 groups showed similar skeletal growth, with the exception of a slightly higher ANS-ME/N-Me in the Class I group. Dental changes were similar in the 2 groups, except that overbite increased slightly more in the Class II group.

Conclusions: Overall, the craniofacial growth patterns of Class I and Class II girls were similar. With growth, the face became more flattened with a decrease of the ANB angle, and the mandible demonstrated forward rotation with decreases of the MP-SN and gonial angles, and an increase of PFH:AFH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajodo.2014.10.023DOI Listing
February 2015

Hepatitis C virus attenuates interferon-induced major histocompatibility complex class I expression and decreases CD8+ T cell effector functions.

Gastroenterology 2014 May 31;146(5):1351-60.e1-4. Epub 2014 Jan 31.

Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea. Electronic address:

Background & Aims: Major histocompatibility complex (MHC) class I-restricted CD8(+) T cells are required for clearance of hepatitis C virus (HCV) infection. MHC class I expression is up-regulated by type I and II interferons (IFNs). However, little is known about the effects of HCV infection on IFN-induced expression of MHC class I.

Methods: We used the HCV cell culture system (HCVcc) with the genotype 2a Japanese fulminant hepatitis-1 strain to investigate IFN-induced expression of MHC class I and its regulatory mechanisms. HCVcc-infected Huh-7.5 cells were analyzed by flow cytometry, metabolic labeling, immunoprecipitation, and immunoblotting analyses. Protein kinase R (PKR) was knocked down with lentiviruses that express small hairpin RNAs. The functional effects of MHC class I regulation by HCV were demonstrated in co-culture studies, using HCV-specific CD8(+) T cells.

Results: Although the baseline level of MHC class I was not affected by HCV infection, IFN-induced expression of MHC class I was notably attenuated in HCV-infected cells. This was associated with replicating HCV RNA, not with viral protein. HCV infection reduced IFN-induced synthesis of MHC class I protein and induced phosphorylation of PKR and eIF2α. IFN-induced MHC class I expression was restored by small hairpin RNA-mediated knockdown of PKR in HCV-infected cells. Co-culture of HCV-specific CD8(+) T cells and HCV-infected cells that expressed HLA-A2 demonstrated that HCV infection reduced the effector functions of HCV-specific CD8(+) T cells; these functions were restored by small hairpin RNA-mediated knockdown of PKR.

Conclusions: IFN-induced expression of MHC class I is attenuated in HCV-infected cells by activation of PKR, which reduces the effector functions of HCV-specific CD8(+) T cells. This appears to be an important mechanism by which HCV circumvents antiviral adaptive immune responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.gastro.2014.01.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478444PMC
May 2014

Trends in antihypertensive medication use and blood pressure control among United States adults with hypertension: the National Health And Nutrition Examination Survey, 2001 to 2010.

Circulation 2012 Oct;126(17):2105-14

Division of Health and Nutrition Examination Surveys, National Center for Health Statistics, Center for Disease Control and Prevention, Room 4333, 3311 Toledo Rd, Hyattsville, MD 20782, USA.

Background: The monitoring of national trends in hypertension treatment and control can provide important insight into the effectiveness of primary prevention efforts for cardiovascular disease. The objective of this study was to examine recent trends in antihypertensive medication use and its impact on blood pressure control among US adults with hypertension.

Methods And Results: A total of 9320 hypertensive people aged ≥18 years from the National Health and Nutrition Examination Survey 2001 to 2010 were included in this study. The prevalence of antihypertensive medication use increased from 63.5% in 2001 to 2002 to 77.3% in 2009 to 2010 (P(trend)<0.01). Most notably, there was a large increase in the use of multiple antihypertensive agents (from 36.8% to 47.7%, P(trend)<0.01). Overall, the use of thiazide diuretics, β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers increased by 23%, 57%, 31%, and 100%, respectively. In comparison with monotherapy, single-pill combinations and multiple-pill combinations were associated with 55% and 26% increased likelihoods of blood pressure control, respectively. By the 2009 to 2010 time period, 47% of all hypertensive people and 60% of treated hypertensive people had blood pressure controlled. However, higher treated but uncontrolled hypertension rates continued to persist among older Americans, non-Hispanic blacks, diabetic people, and those with chronic kidney disease. Also, Mexican Americans with hypertension were still less likely to take antihypertensive medication than non-Hispanic whites with hypertension.

Conclusions: Antihypertensive medication use and blood pressure control among US adults with hypertension significantly increased over the past 10 years. Combination therapy regimens can facilitate achievement of blood pressure goals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.112.096156DOI Listing
October 2012

Blood pressure randomized methodology study comparing automatic oscillometric and mercury sphygmomanometer devices: National Health and Nutrition Examination Survey, 2009-2010.

Natl Health Stat Report 2012 Oct(59):1-15

Objectives: The mercury sphygmomanometer has been the gold standard used for obtaining blood pressure (BP) for the National Health and Nutrition Examination Survey (NHANES) from 1960 to the present. However, due to environmental concerns and an increased use of automated oscillometric BP devices, NHANES has been exploring an alternative to using the standard mercury sphygmomanometer (mercury) to measure BP.

Methods: The accuracy of Omron HEM-907XL BP readings was compared with that of mercury BP device readings for gender, age group, race and ethnicity, and body mass index categories and cuff-size subgroups. Each person had three BP measurements per device recorded sequentially. The order of the devices and readers were randomly assigned. A total of 6,460 participants had three valid systolic readings, and 6,338 had three valid diastolic readings.

Results: Omron and mercury measurements were correlated (r = 0.92, systolic BP; r = 0.79, diastolic BP). Overall, the mean between-device differences (Omron and mercury) were -1.6 mm Hg for systolic and -0.6 mm Hg for diastolic (p < 0.05 for both). The mean between-device differences were less than or about 2 mm Hg for each subgroup: gender, age group, race and ethnicity, and body mass index categories, and cuff-size subgroups. The exceptions were mean systolic between-device differences for those using the extra-large BP cuff (-3.1 mm Hg) and obese individuals (-2.6 mm Hg), and the mean diastolic between-device differences for the underweight group (-3.5 mm Hg). Assuming mercury to be the gold standard, between-device agreements for the frequency of high BP (140/90 mm Hg or more) and stage II high BP (160/100 mm Hg or more) were above chance (kappa = 0.72 for both). Omron underestimated the high BP frequency by 2.28% and stage II high BP frequency by 0.77%.

Conclusions: Lower estimates of high BP by the Omron device may require adjusting future national prevalence estimates accordingly to account for between-device differences.
View Article and Find Full Text PDF

Download full-text PDF

Source
October 2012

Adiponectin, a downstream target gene of peroxisome proliferator-activated receptor γ, controls hepatitis B virus replication.

Virology 2011 Jan 6;409(2):290-8. Epub 2010 Nov 6.

Department of Microbiology, Ajou University School of Medicine, Woncheon-dong 5, Suwon 442-721, South Korea.

In this study, HepG2-hepatitis B virus (HBV)-stable cells that did not overexpress HBx and HBx-deficient mutant-transfected cells were analyzed for their expression of HBV-induced, upregulated adipogenic and lipogenic genes. The mRNAs of CCAAT enhancer binding protein α (C/EBPα), peroxisome proliferator-activated receptor γ (PPARγ), adiponectin, liver X receptor α (LXRα), sterol regulatory element binding protein 1c (SREBP1c), and fatty acid synthase (FAS) were expressed at higher levels in HepG2-HBV and lamivudine-treated stable cells and HBx-deficient mutant-transfected cells than in the HepG2 cells. Lamivudine treatment reduced the mRNA levels of PPARγ and C/EBPα. Conversely, HBV replication was upregulated by adiponectin and PPARγ agonist rosiglitazone treatments and was downregulated by adiponectin siRNAs. Collectively, our results demonstrate that HBV replication and/or protein expression, even in the absence of HBx, upregulated adipogenic or lipogenic genes, and that the control of adiponectin might prove useful as a therapeutic modality for the treatment of chronic hepatitis B.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.virol.2010.10.024DOI Listing
January 2011

STAT3 transcriptional factor activated by reactive oxygen species induces IL6 in starvation-induced autophagy of cancer cells.

Autophagy 2010 Nov 16;6(8):1125-38. Epub 2010 Nov 16.

Department of Microbiology, Ajou University School of Medicine, Suwon, Korea.

Autophagy is one of the survival processes of cancer cells, especially in stressful conditions such as starvation, hypoxia and chemotherapeutic agents. However, its roles in tumor survival have not yet been fully elucidated. Here, we found for the first time that JAK2/STAT3 was activated in HeLa cells when they were starved or treated with rapamycin. STAT3 activation was associated with autophagic processes, because it was completely inhibited by 3-methyladenine, partially inhibited by knockdown of molecules associated with autophagic processes and blocked by antioxidants, DPI, a Nox inhibitor and knockdown of p22 phox, indicating that ROS generated by Nox that was activated during autophagic processes activated JAK2/STAT3 pathway. Activated STAT3 directly bound to IL6 promoter and increased IL6 mRNA and protein secretion. Finally, the conditioned media, which included IL6, from starved HeLa cells promoted cancer cell survival in both normal and starved conditions, confirmed by clonogenic, proliferation and cell death assays. These data together indicate that the autophagic process in cancer cells can contribute to their survival by JAk2/STAT3 activation and subsequent secretion of growth factors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4161/auto.6.8.13547DOI Listing
November 2010

Phosphatidylinositol 4-phosphate 5-kinase alpha is induced in ganglioside-stimulated brain astrocytes and contributes to inflammatory responses.

Exp Mol Med 2010 Sep;42(9):662-73

Department of Microbiology, Ajou University School of Medicine, Suwon 443-721, Korea.

In brain tissue, astrocytes play defensive roles in central nervous system integrity by mediating immune responses against pathological conditions. Type I phosphatidylinositol 4-phosphate 5-kinase alpha (PIP5K alpha) that is responsible for production of phosphatidylinositol 4,5-bisphosphate (PI[4,5]P2) regulates many important cell functions at the cell surface. Here, we have examined whether PIP5K alpha is associated with astrocyte inflammatory responses. Gangliosides are releasable from damaged cell membranes of neurons and capable of inducing inflammatory responses. We found that treatment of primary cultured astrocytes with gangliosides significantly enhanced PIP5K alpha mRNA and protein expression levels. PI(4,5)P2 imaging using a fluorescent tubby (R332H) expression as a PI(4,5)P2-specific probe showed that ganglioside treatment increased PI(4,5)P2 level. Interestingly, microRNA-based PIP5K alpha knockdown strongly reduced ganglioside-induced transcription of proinflammatory cytokines IL-1 beta and TNFalpha. PIP5K alpha knockdown also suppressed ganglioside-induced phosphorylation and nuclear translocation of NF-kappaB and the degradation of I kappaB-alpha, indicating that PIP5K alpha knockdown interfered with the ganglioside-activated NF-kappaB signaling. Together, these results suggest that PIP5K alpha is a novel inflammatory mediator that undergoes upregulation and contributes to immune responses by facilitating NF-kappaB activation in ganglioside-stimulated astrocytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947023PMC
http://dx.doi.org/10.3858/emm.2010.42.9.066DOI Listing
September 2010

High blood pressure and cardiovascular disease mortality risk among U.S. adults: the third National Health and Nutrition Examination Survey mortality follow-up study.

Ann Epidemiol 2008 Apr 8;18(4):302-9. Epub 2008 Feb 8.

Division of Health and Nutrition Examination Surveys, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, MD 20782, USA.

Purpose: We sought to examine whether prehypertension is associated with increased cardiovascular disease (CVD) mortality risk and whether the association of blood pressure with CVD outcome is modified by social demographics or hypertension treatment and control.

Methods: Data from the Third National Health and Nutrition Examination Survey and mortality follow-up through 2000 were used to estimate the relative risk of death from CVD associated with hypertension and prehypertension, after adjusting for confounding and modifying factors.

Results: Compared with normotension, the relative risks of CVD mortality were 1.23 (95% confidence interval [95% CI] 0.85-1.79, p=0.26) for prehypertension, 1.64 (95% CI 1.11-2.41, p=0.01) for hypertension, 1.74 (95% CI 1.28-2.49, p=0.007) for uncontrolled hypertension, and 1.15 (95% CI 0.79-1.80, p=0.53) for controlled hypertension. Hypertensive adults <65 years and non-Hispanic blacks had a 3.86-fold and a 4.65-fold increased CVD mortality risk respectively. Age, gender, and race/ethnicity stratified analyses showed no associations between prehypertension and CVD mortality. However, blood pressure at a high range of prehypertension (130-139/84-89 mmHg) was associated with increased risk of CVD mortality (hazard ratio 1.41, p<0.05) relative to blood pressure less than 120/80 mmHg.

Conclusions: This study supports a strong, significant, and independent association of elevated blood pressure with CVD mortality risk. Hypertension continued to greatly increase CVD morality risk, particularly among persons <65 years and non-Hispanic blacks. Treatment and control of hypertension eliminated the excess CVD mortality risk observed among the hypertension population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.annepidem.2007.11.013DOI Listing
April 2008

Regional differences in African Americans' high risk for stroke: the remarkable burden of stroke for Southern African Americans.

Ann Epidemiol 2007 Sep;17(9):689-96

University of Alabama School of Public Health, Department of Biostatistics, Birmingham, AL 35294-0022, USA.

Purpose: The stroke mortality rate for African Americans aged 45 to 64 years is 3 to 4 times higher than for whites of the same age, with a decreasing black-to-white mortality ratio with increasing age. There is also a "STROKE BELT" with higher stroke mortality in the southeastern United States. This study assesses if there are also geographic variations in the magnitude of the excess stroke mortality for African Americans.

Methods: The age- and sex-specific black-to-white mortality ratio was calculated for each of 26 states with a sufficient African American population for stable estimates. The southern excess was calculated as the percentage excess of southern over nonsouthern rates.

Results: Across age and sex strata, the black-to-white stroke mortality ratio was consistently higher for southern states, with an average black-to-white stroke mortality ratio that ranged from 6% to 21% higher among southern states than in nonsouthern states.

Conclusions: The increase in stroke mortality rates for African Americans in southern states is even larger than expected. That southern states that are not part of the "STROKE BELT" (Virginia and Florida) also have an elevated black-to-white mortality ratio suggests the mechanism of higher risk for African Americans may be independent of the causes contributing to "STROKE BELT."
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.annepidem.2007.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1995237PMC
September 2007

Up-regulation of acetyl-CoA carboxylase alpha and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells.

J Biol Chem 2007 Sep 13;282(36):26122-31. Epub 2007 Jul 13.

Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Science, Institute of Genetic Science, Center for Chronic Metabolic Disease Research, Seoul, Korea.

Expression of the HER2 oncogene is increased in approximately 30% of human breast carcinomas and is closely correlated with the expression of fatty acid synthase (FASN). In the present study, we determined the mechanism by which FASN and acetyl-CoA carboxylase alpha (ACCalpha) could be induced by HER2 overexpression. SK-BR-3 and BT-474 cells, breast cancer cells that overexpress HER2, expressed higher levels of FASN and ACCalpha compared with MCF-7 and MDA-MB-231 breast cancer cells in which HER2 expression is low. The induction of FASN and ACCalpha in BT474 cells were not mediated by the activation of SREBP-1. Exogenous HER2 expression in MDA-MB-231 cells induced the expression of FASN and ACCalpha, and the HER2-mediated increase in ACCalpha and FASN was inhibited by both LY294002, a phosphatidylinositol 3-kinase inhibitor, and rapamycin, a mammalian target of rapamycin (mTOR) inhibitor. In addition, the activation of mTOR by the overexpression of RHEB in MDA-MB-231 cells increased the synthetic rates of both FASN and ACCalpha. On the other hand, FASN and ACCalpha were reduced in BT-474 cells by a blockade of the mTOR signaling pathway. These changes observed in their protein levels were not accompanied by changes in their mRNA levels. The 5'- and 3'-untranslated regions of both FASN and ACCalpha mRNAs were involved in selective translational induction that was mediated by mTOR signal transduction. These results strongly suggest that the major mechanism of HER2-mediated induction of FASN and ACCalpha in the breast cancer cells used in this study is translational regulation primarily through the mTOR signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.M702854200DOI Listing
September 2007

Trends in hypertension prevalence, awareness, treatment, and control in older U.S. adults: data from the National Health and Nutrition Examination Survey 1988 to 2004.

J Am Geriatr Soc 2007 Jul;55(7):1056-65

Division of Health Nutrition Examination Statistics, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Maryland 20782, USA.

Objectives: To describe hypertension trends in U.S. adults aged 60 and older using National Health and Nutrition Examination Survey (NHANES) data.

Setting: NHANES III (1988-1994) and NHANES 1999 to 2004.

Design: Cross-sectional nationally representative health examination survey.

Participants: Participants in NHANES III (n=5,093) and NHANES 1999 to 2004 (n=4,710).

Measurements: Blood pressure (BP).

Results: In 1999 to 2004, 67% of U.S. adults aged 60 and older years were hypertensive, an increase of 10% from NHANES III. Between 1988 to 1994 and 1999 to 2004, hypertension control increased for men from 39% to 51% (P<.05) but remained unchanged for women (35% to 37%; P>.05). Non-Hispanic black men and women had higher prevalences of hypertension than non-Hispanic whites (odds ratio (OR)=2.54, 95% confidence interval (CI)=1.90-3.40 and OR=2.07, 95% CI=1.31-3.26, respectively), but men were less likely to have controlled BP (OR=0.60, 95% CI=0.41-0.86). Mexican-American men and women were less likely than non-Hispanic whites to have controlled BP (OR=0.55, 95% CI=0.33-0.91 and OR=0.63, 95% CI=0.40-0.98, respectively). Women and men aged 70 and older were significantly less likely to control their hypertension than those aged 60 to 69. In addition, women aged 70 and older were significantly less aware and treated. Having BP measured within 6 months was significantly associated with greater awareness, greater treatment in men and women, and greater control in women. A history of diabetes mellitus or chronic kidney disease (CKD) was significantly associated with less hypertension control.

Conclusion: There was a significant increase in hypertension prevalence from 1988 to 2004. Hypertension control continues to be problematic for women, persons aged 70 and older, non-Hispanic blacks and Mexican Americans, and individuals with diabetes mellitus and CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1532-5415.2007.01215.xDOI Listing
July 2007

In vivo magnetic resonance detection of cancer by using multifunctional magnetic nanocrystals.

J Am Chem Soc 2005 Sep;127(35):12387-91

Yonsei Nano-Medical Core Research Center, Department of Radiology, Yonsei University, Seoul 120-752, Korea.

The unique properties of magnetic nanocrystals provide them with high potential as key probes and vectors in the next generation of biomedical applications. Although superparamagnetic iron oxide nanocrystals have been extensively studied as excellent magnetic resonance imaging (MRI) probes for various cell trafficking, gene expression, and cancer diagnosis, further development of in vivo MRI applications has been very limited. Here, we describe in vivo diagnosis of cancer, utilizing a well-defined magnetic nanocrystal probe system with multiple capabilities, such as small size, strong magnetism, high biocompatibility, and the possession of active functionality for desired receptors. Our magnetic nanocrystals are conjugated to a cancer-targeting antibody, Herceptin, and subsequent utilization of these conjugates as MRI probes has been successfully demonstrated for the monitoring of in vivo selective targeting events of human cancer cells implanted in live mice. Further conjugation of these nanocrystal probes with fluorescent dye-labeled antibodies enables both in vitro and ex vivo optical detection of cancer as well as in vivo MRI, which are potentially applicable for an advanced multimodal detection system. Our study finds that high performance in vivo MR diagnosis of cancer is achievable by utilizing improved and multifunctional material properties of iron oxide nanocrystal probes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ja052337cDOI Listing
September 2005

Nanoscale size effect of magnetic nanocrystals and their utilization for cancer diagnosis via magnetic resonance imaging.

J Am Chem Soc 2005 Apr;127(16):5732-3

Department of Chemistry, Yonsei University, Seoul 120-749, Korea.

Since the use of magnetic nanocrystals as probes for biomedical system is attractive, it is important to develop optimal synthetic protocols for high-quality magnetic nanocrystals and to have the systematic understanding of their nanoscale properties. Here we present the development of a synthetically controlled magnetic nanocrystal model system that correlates the nanoscale tunabilities in terms of size, magnetism, and induced nuclear spin relaxation processes. This system further led to the development of high-performance nanocrystal-antibody probe systems for the diagnosis of breast cancer cells via magnetic resonance imaging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/ja0422155DOI Listing
April 2005

Alternative usages of multiple promoters of the acetyl-CoA carboxylase beta gene are related to differential transcriptional regulation in human and rodent tissues.

J Biol Chem 2005 Feb 6;280(7):5909-16. Epub 2004 Dec 6.

Department of Biochemistry and Molecular Biology, Brain Korea 21 Project for Medical Science, Institute of Genetic Science, Yonsei University College of Medicine, 134 Shinchondong Seodaemungu, Seoul 120-752, Korea.

Acetyl-CoA carboxylase beta (ACCbeta) is a critical enzyme in the regulation of fatty acid oxidation and is dominantly expressed in the skeletal muscle, heart, and liver. It has been established that two promoters, P-I and P-II, control the transcription of the ACCbeta gene. However, the precise mechanism involved in controlling tissue-specific gene expression of ACCbeta is largely unknown yet. In this study we revealed that promoter P-I, active in the skeletal muscle and heart but not in the liver, could be activated by myogenic regulatory factors and retinoid X receptors in a synergistic manner. Moreover, P-I was also activated markedly by the cardiac-specific transcription factors, Csx/Nkx2.5 and GATA4. These results suggest that the proper stimulation of P-I by these tissue-specific transcription factors is important for the expression of ACCbeta according to the tissue types. In addition, CpG sites around human exon 1a transcribed by P-I are half-methylated in muscle but completely methylated in the liver, where P-I is absolutely inactive. In humans, the skeletal muscle uses P-II as well as P-I, whereas only P-I is active in rat skeletal muscle. The proximal myogenic regulatory factor-binding sites in human P-II, which are not conserved in rat P-II, might contribute to this difference in P-II usage between human and rat skeletal muscle. Hepatoma-derived cell lines primarily use another novel promoter located about 3 kilobases upstream of P-I, designated as P-O. This study is the first to explain the mechanisms underlying the differential regulation of ACCbeta gene expression between tissues in living organisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.M409037200DOI Listing
February 2005

CCAAT/enhancer binding protein and nuclear factor-Y regulate adiponectin gene expression in adipose tissue.

Diabetes 2004 Nov;53(11):2757-66

Department of BiochemistryMolecular Biology, Institute of Genetic Science, Seoul, Korea.

Adiponectin is one of the adipokines secreted by adipocytes and regulates energy homeostasis associated with insulin sensitivity, suggesting a possibility of nutritional regulation of adiponectin gene expression. In this study, we showed that the transcription of adiponectin gene was induced 4-6 h after refeeding of mice. Also, differentiated 3T3-L1 adipocytes that were treated with high glucose expressed significantly increased adiponectin mRNA. Promoter analysis using nuclear extracts from white adipose tissue revealed that CCAAT/enhancer binding protein (C/EBP) and nuclear factor-Y (NF-Y) bound on the -117/-73 region of the adiponectin promoter. This region was critical for the activity of the adiponectin promoter as the deletion or mutation of this region markedly diminished the promoter activity to a basal level. Furthermore, the C/EBP binding increased in both refed animal and high glucose-treated 3T3-L1 adipocytes in an electrophoretic mobility shift assay, suggesting that C/EBP is responsible for the dietary response of the adiponectin gene expression. Chromatin immunoprecipitation studies demonstrated the binding of C/EBP and NF-Y in both mouse and differentiated 3T3-L1 adipocytes and also that C/EBP binding increased in response to high glucose. These findings demonstrated that C/EBP and NF-Y are critical for the regulation of the adiponectin expression in response to nutrients and in the course of adipocyte differentiation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/diabetes.53.11.2757DOI Listing
November 2004

Expression of mitochondria-dependent apoptosis genes (p53, Bax, and Bcl-2) in rat granulosa cells during follicular development.

J Soc Gynecol Investig 2004 Jul;11(5):311-7

Department of Obstetrics and Gynecology, Sungkyunkwan University School of Medicine, Samsung Medical Center, 50 Irwon-dong Gangnam-gu, Seoul 135-710, South Korea.

Objective: We examined rat ovarian granulosa cells at different follicular stages and evaluated the apoptosis pattern of the mitochondria-dependent genes during folliculogenesis.

Methods: After down-regulating ovarian function with gonadotropin-releasing hormone agonist (GnRHa), granulosa cells were collected from the rat ovary at different stages of the following different hormonal treatment paradigms: stage E (after estrogen treatment), EF (after E + follicle-stimulating hormone [FSH] treatment), and EF hCG (after E + FSH + human chorionic gonadotropin treatment). To evaluate the in vitro susceptibility of granulosa cells at different developmental stages to apoptosis, the collected cells were cultured in a serum-free medium with or without E2 for 24 hours. The regulation of apoptosis in the granulosa cells was analyzed using fluorescein-activated cell sorting, quantitative competitive polymerase chain reaction, and western blot methods.

Results: The apoptosis rate of the freshly isolated granulosa cells tended to increase according to the hormonal treatment paradigm. In addition, during the hormone treatment, mitochondria-dependent apoptosis genes showed the following changes: although the Bax mRNA level did not change, the Bcl-2 mRNA level decreased significantly (P <.05). The p53 mRNA level increased significantly (P <.05) and closely matched the apoptosis rate (R = 0.7, P <.05). The expression of the active form of the caspase-3 protein (the final executioner of cell death) tended to increase and showed a good correlation with the apoptosis rate (R = 0.96, P <.01). After an in vitro culture of the granulosa cells, the apoptosis rate tended to increase at all stages, particularly stage EF hCG (P <.05). Bax and p53 mRNA tended to increase and showed a good correlation with the apoptosis rate (R = 0.64, P <.05 and 0.86, P <.01). The Bcl-2 mRNA level tended to decrease at all stages showing no correlation with the apoptosis rate. The expression level of the active caspase-3 protein tended to increase at all stages and showed a good correlation with the apoptosis rate (R = 0.93, P <.01).

Conclusion: Apoptosis of rat ovarian granulosa cells tends to increase according to the stage of follicular development. Among the mitochondria-dependent genes, p53 closely correlates with granulosa cell apoptosis during follicular development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jsgi.2004.01.015DOI Listing
July 2004

Effects of HMGB-1 overexpression on cell-cycle progression in MCF-7 cells.

J Korean Med Sci 2004 Jun;19(3):321-6

Center for Clinical Medicine & Samsung Biomedical Research Institute, University School of Medicine, Seoul, Korea.

High mobility group-1 (HMGB-1) enhances the DNA interactions and possesses a transcriptional activation potential for several families of sequence-specific transcriptional activators. In order to examine the effect of HMGB-1 on the cell cycle progression in MCF-7 cells, the HMGB-1 expression vector was transfected into synchronized MCF-7 cells, and the effect of HMGB-1 overexpression on the cell cycle was examined. The HMGB-1 protein level in the transfected cells increased 4.87-fold compared to the non-transfected cells. There were few changes in the cell cycle phase distribution after HMGB-1 overexpression in the MCF-7 cells. Following the estrogen treatment, the cell cycle progressed in both the HMGB-1 overexpressed MCF-7 and the mock-treated cells. However, a larger proportion of HMGB-1 overexpressing MCF-7 cells progressed to the either S or G2 phase than the mock-treated cells. The mRNA levels of the cell cycle regulators changed after being treated with estrogen in both the HMGB-1 overexpressing MCF-7 and the mock-treated cells, but the changes in the expression level of the cell cycle regulator genes were more prominent in the HMGB-1 overexpressing MCF-7 cells than in the mock-treated cells. In conclusion, HMGB-1 overexpression itself does not alter the MCF-7 cell cycle progression, but the addition of estrogen to the HMGB-1 overexpressing MCF-7 cells appears to accelerate the cell cycle progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2816829PMC
http://dx.doi.org/10.3346/jkms.2004.19.3.321DOI Listing
June 2004
-->