열공성 뇌경색과 뇌내출혈의 위험인자 비교

이장준,이현아,최종환,이형,임정근,이상도,박영춘 계명대학교 의과학연구소 2000 계명의대학술지 Vol.19 No.2

Cerebral small vessel disease is the most important cause of lacunar infarction (LI) and intracerebral hemorrhage (ICH). It is generally postulated that, in its early stages, the vascular lesion engenders vessel wall fragility and ICH. But if rupture dose not occur, segmental vessel occlusion evolves, producing LI. It may be a common aging phenomenon that is exacerbated by hypertension and diabetes mellitus. This study was performed to evaluate risk factors of LI and ICH. We reviewed retrospectively the medical records of 690 patients (254 LI, 436 ICH) with stroke who were admitted to Keimyung University Dongsan Medical Center from January 1995 to December 1998. The major risk factors including age, sex, hypertension, diabetes mellitus and several minor risk factors were analyzed in these patients. Older age (p<0.01), male sex(p<0.01), hypertension with treatment(p<0.01), hypertension with long duration(p<0.01) and hypertriglyceridemia(p<0.01), cigarette smoking(p<0.01) were significantly more frequent in LI. Younger age(p<0.01), female sex(p<0.01) and hypertension without treatment(p<0.01), hypertension with short duration(p<0.01) were more frequent in ICH. The prevalence, duration and treatment of diabetes mellitus were not different between these two groups. This study show that the age, sex, treatment of hypertension, duration of hypertension and cigarette smoking seem to be significant risk factors between LI and ICH.

HP1β suppresses metastasis of human cancer cells by decreasing the expression and activation of MMP2.

Yi, Sang Ah,Ryu, Hyun-Wook,Lee, Dong Hoon,Han, Jeung-Whan,Kwon, So Hee Lychnia 2014 International journal of oncology Vol.45 No.6

<P>Heterochromatin protein 1 (HP 1) is an epigenetic modifier of gene regulation and chromatin packing via binding to trimethylated histone H3 lysine 9 (H3K9). HP1 plays an important role in gene activation as well as gene repression in heterochromatin and euchromatin. However, the role of individual HP1 proteins in human diseases remains elusive. Here, we show that HP1 beta negatively regulates the expression and activation of matrix metallopeptidase (MMP)2, which mediates cancer metastasis by destructing type IV collagen. Reduced HP1 beta expression correlates with the increased level of pro- and active-MMP2 in colon cancer cells. Consistently, HP1 beta knockdown (KD) increased and HP1 beta overexpression decreased the mRNA level of MMP2 and membrane type 1 metallopeptidase (MT1-MMP). Furthermore, cancer cells overexpressing HP1 beta showed impaired migratory ability, whereas HP1 beta-deleted cancer cells had increased migration. HP1 beta negatively regulates MMP2 expression in a transcriptional level and prevents MMP2 activation through reducing the expression of MT1-MMP. These findings shed new light on HP1 beta as a molecular regulator and an efficient therapeutic target of metastatic cancer.</P>

Fermented ginseng extract, BST204, disturbs adipogenesis of mesenchymal stem cells through inhibition of S6 kinase 1 signaling

Yi, Sang Ah,Lee, Jieun,Park, Sun Kyu,Kim, Jeom Yong,Park, Jong Woo,Lee, Min Gyu,Nam, Ki Hong,Park, Jee Hun,Oh, Hwamok,Kim, Saetbyul,Han, Jihoon,Kim, Bo Kyung,Jo, Dong-Gyu,Han, Jeung-Whan The Korean Society of Ginseng 2020 Journal of Ginseng Research Vol.44 No.1

Background: The biological and pharmacological effects of BST204, a fermented ginseng extract, have been reported in various disease conditions. However, its molecular action in metabolic disease remains poorly understood. In this study, we identified the antiadipogenic activity of BST204 resulting from its inhibition of the S6 kinase 1 (S6K1) signaling pathway. Methods: The inhibitory effects of BST204 on S6K1 signaling were investigated by immunoblot, nuclear fractionation, immunoprecipitation analyses. The antiadipogenic effect of BST204 was evaluated by measuring mRNA levels of adipogenic genes and by chromatin immunoprecipitation and quantitative real-time polymerase chain reaction analysis. Results: Treatment with BST204 inhibited activation and nuclear translocation of S6K1, further decreasing the interaction between S6K1 and histone H2B in 10T1/2 mesenchymal stem cells. Subsequently, phosphorylation of H2B at serine 36 (H2BS36p) by S6K1 was reduced by BST204, inducing an increase in the mRNA expression of Wnt6, Wnt10a, and Wnt10b, which disturbed adipogenic differentiation and promoted myogenic and early osteogenic gene expression. Consistently, BST204 treatment during adipogenic commitment suppressed the expression of adipogenic marker genes and lipid drop formation. Conclusion: Our results indicate that BST204 blocks adipogenesis of mesenchymal stem cells through the inhibition of S6K1-mediated histone phosphorylation. This study suggests the potential therapeutic strategy using BST204 to combat obesity and musculoskeletal diseases.

S6K1 controls adiponectin expression by inducing a transcriptional switch: BMAL1-to-EZH2

Yi Sang Ah,Jeon Ye Ji,Lee Min Gyu,Nam Ki Hong,Ann Sora,Lee Jaecheol,Han Jeung-Whan 생화학분자생물학회 2022 Experimental and molecular medicine Vol.54 No.-

Adiponectin (encoded by Adipoq), a fat-derived hormone, alleviates risk factors associated with metabolic disorders. Although many transcription factors are known to control adiponectin expression, the mechanism underlying its fluctuation with regard to metabolic status remains unclear. Here, we show that ribosomal protein S6 kinase 1 (S6K1) controls adiponectin expression by inducing a transcriptional switch between two transcriptional machineries, BMAL1 and EZH2. Active S6K1 induced a suppressive histone code cascade, H2BS36p-EZH2-H3K27me3, leading to suppression of adiponectin expression. Moreover, active S6K1 phosphorylated BMAL1, an important transcription factor regulating the circadian clock system, at serine 42, which led to its dissociation from the Adipoq promoter region. This response resulted in EZH2 recruitment and subsequent H3K27me3 modification of the Adipoq promoter. Upon fasting, inactivation of S6K1 induced the opposite transcriptional switch, EZH2-to-BMAL1, promoting adiponectin expression. Consistently, S6K1-depleted mice exhibited lower H3K27me3 levels and elevated adiponectin expression. These findings identify a novel epigenetic switch system by which S6K1 controls the production of adiponectin, which displays beneficial effects on metabolism.

Epigenetic role of nuclear S6K1 in early adipogenesis

( Sang Ah Yi ),( Jihoon Han ),( Jeung Whan Han ) 생화학분자생물학회(구 한국생화학분자생물학회) 2016 BMB Reports Vol.49 No.8

S6K1 is a key regulator of cell growth, cell size, and metabolism. Although the role of cytosolic S6K1 in cellular processes is well established, the function of S6K1 in the nucleus remains poorly understood. Our recent study has revealed that S6K1 is translocated into the nucleus upon adipogenic stimulus where it directly binds to and phosphorylates H2B at serine 36. Such phosphorylation promotes EZH2 recruitment and subsequent histone H3K27 trimethylation on the promoter of its target genes including Wnt6, Wnt10a, and Wnt10b, leading to repression of their expression. S6K1-mediated suppression of Wnt genes facilitates adipogenic differentiation through the expression of adipogenic transcription factors PPARγ and Cebpa. White adipose tissues from S6K1-deficient mice consistently exhibit marked reduction in H2BS36 phosphorylation (H2BS36p) and H3K27 trimethylation (H3K27me3), leading to enhanced expression of Wnt genes. In addition, expression levels of H2BS36p and H3K27me3 are highly elevated in white adipose tissues from mice fed on high-fat diet or from obese humans. These findings describe a novel role of S6K1 as a transcriptional regulator controlling an epigenetic network initiated by phosphorylation of H2B and trimethylation of H3, thus shutting off Wnt gene expression in early adipogenesis. [BMB Reports 2016; 49(8): 401-402]

Fermented ginseng extract, BST204, disturbs adipogenesis of mesenchymal stem cells through inhibition of S6 kinase 1 signaling

Sang Ah Yi,Jieun Lee,Sun Kyu Park,Jeom Yong Kim,Jong Woo Park,Min Gyu Lee,Ki Hong Nam,Jee Hun Park,Hwamok Oh,Saetbyul Kim,Jihoon Han,Bo Kyung Kim,Dong-Gyu Jo,Jeung-Whan Han 고려인삼학회 2020 Journal of Ginseng Research Vol.44 No.1

Background: The biological and pharmacological effects of BST204, a fermented ginseng extract, havebeen reported in various disease conditions. However, its molecular action in metabolic disease remainspoorly understood. In this study, we identified the antiadipogenic activity of BST204 resulting from itsinhibition of the S6 kinase 1 (S6K1) signaling pathway. Methods: The inhibitory effects of BST204 on S6K1 signaling were investigated by immunoblot, nuclearfractionation, immunoprecipitation analyses. The antiadipogenic effect of BST204 was evaluated bymeasuring mRNA levels of adipogenic genes and by chromatin immunoprecipitation and quantitativereal-time polymerase chain reaction analysis. Results: Treatment with BST204 inhibited activation and nuclear translocation of S6K1, furtherdecreasing the interaction between S6K1 and histone H2B in 10T1/2 mesenchymal stem cells. Subsequently,phosphorylation of H2B at serine 36 (H2BS36p) by S6K1 was reduced by BST204, inducing anincrease in the mRNA expression of Wnt6, Wnt10a, and Wnt10b, which disturbed adipogenic differentiationand promoted myogenic and early osteogenic gene expression. Consistently, BST204 treatmentduring adipogenic commitment suppressed the expression of adipogenic marker genes and lipid dropformation. Conclusion: Our results indicate that BST204 blocks adipogenesis of mesenchymal stem cells through theinhibition of S6K1-mediated histone phosphorylation. This study suggests the potential therapeuticstrategy using BST204 to combat obesity and musculoskeletal diseases.

허혈성뇌졸중과 출혈성뇌졸중에서 Apolipoprotein E 유전자의 다형성

이현아(Hyon-Ah Yi),임정근(Jeong-Geun Lim),권오대(Oh-Dae Kwon),조용원(Yong-Won Cho),이형(Hyung Lee),이상도(Sang-Doe Yi),김대광(Dae-Kwang Kim) 대한해부학회 2002 Anatomy & Cell Biology Vol.35 No.4

Apolipoprotein E (APOE) 대립유전자의 분포는 동맥경화증, 심장동맥질환 및 목동맥협착증 환자에서 일반 인구군에 비해 유의한 차이를 나타내는 것으로 알려져 있지만, 뇌졸중에서의 역할에 대해서는 명확하게 알려져 있지 않다. 이 연구는 뇌경색과 뇌출혈에서 APOE 유전자의 다형성을 조사하고 APOE 대립유전자와 뇌졸중의 발생 및 유형과의 상관관계를 알아 보기 위해 시행하였다. 113명의 뇌졸중 환자군과 111명의 대조군을 대상으로 APOE 대립유전자의 분포 및 유전자형을 조사하고 뇌혈관질환과 이들 사이의 상관관계를 분석하였다. 대상군과 대조군, 그리고 뇌출혈군과 뇌경색군 사이에 APOE 대립유전자와 APOE 유전자형의 분포는 유의한 차이가 없 었다. 따라서 뇌졸중 환자군에서 APOE의 다형성이 뇌졸중의 발생과 유형에 영향을 끼치지 않는 것으로 추정된다. 이는 지역적 차이와 표본 추출 상태 및 표본 수의 영향을 고려해야 함이므로 뇌졸중의 유전적 병태 생리를 이해하기 위해서 더 많은 표본을 대상으로 한 연구가 필요할 것이다. There is an evidence for a role of apolipoprotein E (APOE) in atherosclerosis, coronary heart disease and carotid artery stenosis. Morbidity of carotid artery atherosclerosis is higher in persons carrying an ε4 allele, but the association of cerebrovascular disease and apoE genotype is controversial. We studied the association between APOE genotype and allele (ε2, ε3, ε4) frequency and stroke. We evaluated APOE genotype in 133 first-ever stroke patients and 111 healthy controls. We also estimated the risk factors of stroke such as hypertension, diabetes and lipid profiles in both groups. APOE genotypes were analyzed by polymerase chain reaction. APOE genotypes and allele distributions were not different in patients and controls. There is also no difference of APOE allele frequencies between ischemic small artery occlusive disease and hypertensive subcortical intracerebral hemorrhage. We concluded that the APOE-ε4 allele is not associated with stoke including ischemic and hemorrhagic stroke.

Epigenetic Activation of the <i>Foxa2</i> Gene Is Required for Maintaining the Potential of Neural Precursor Cells to Differentiate into Dopaminergic Neurons After Expansion

Bang, So-Young,Kwon, So Hee,Yi, Sang-Hoon,Yi, Sang Ah,Park, Eun Kyung,Lee, Jae-Cheol,Jang, Choon-Gon,You, Jueng Soo,Lee, Sang-Hun,Han, Jeung-Whan Mary Ann Liebert 2015 STEM CELLS AND DEVELOPMENT Vol.24 No.4

<P>Dysregulation of forkhead box protein A2 (Foxa2) expression in fetal ventral mesencephalon (VM)-derived neural precursor cells (NPCs) appears to be associated with the loss of their potential to differentiate into dopaminergic (DA) neurons after mitogenic expansion in vitro, hindering their efficient use as a transplantable cell source. Here, we report that epigenetic activation of Foxa2 in VM-derived NPCs by inducing histone hyperacetylation rescues the mitogenic-expansion-dependent decrease of differentiation potential to DA neurons. The silencing of Foxa2 gene expression after expansion is accompanied by repressive histone modifications, including hypoacetylation of histone H3 and H4 and trimethylation of H3K27 on the Foxa2 promoter, as well as on the global level. In addition, histone deacetylase 7 (HDAC7) is highly expressed during differentiation and recruited to the Foxa2 promoter. Induction of histone acetylation in VM-derived NPCs by either knockdown of HDAC7 or treatment with the HDAC inhibitor apicidin upregulates Foxa2 expression via hyperacetylation of H3 and a decrease in H3K27 trimethylation on the promoter regions, leading to the expression of DA neuron developmental genes and enhanced differentiation of DA neurons. These effects are antagonized by the expression of shRNAs specific for Foxa2 but enhanced by shRNA for HDAC7. Collectively, these findings indicate that loss of differentiation potential of expanded VM-derived NPCs is attributed to a decrease in Foxa2 expression and suggest that activation of the endogenous Foxa2 gene by epigenetic regulation might be an approach to enhance the generation of DA neurons.</P>

Analysis of latent tuberculosis infection of patients with psoriasis receiving biologic treatment in Korea with serial interferon-gamma release assay results

( Sung Min Kim ),( Jae Young Sung ),( Yi Na Yun ),( Hyung Seok Son ),( Chang Yong Kim ),( Young Ah Cho ),( Ji Su Lee ),( Da-ae Yu ),( Yang Won Lee ),( Yong Beom Choe ) 대한피부과학회 2022 대한피부과학회 학술발표대회집 Vol.74 No.1

Screening for depression and anxiety disorder in children with headache

Lee, Sang Mi,Yoon, Jung-Rim,Yi, Yoon Young,Eom, Soyong,Lee, Joon Soo,Kim, Heung Dong,Cheon, Keun-Ah,Kang, Hoon-Chul The Korean Pediatric Society 2015 Clinical and Experimental Pediatrics (CEP) Vol.58 No.2

Purpose: The purpose of this study was to investigate the importance of initial screening tests for depression and anxiety disorders in children with headache. In addition, this study evaluated whether the Children's Depression Inventory (CDI) and Revised Children's Manifest Anxiety Scale (RCMAS) are suitable for screening symptoms of depression and anxiety. Methods: A retrospective chart review was conducted of 720 children aged 7-17 years who had visited a pediatric neurology clinic for headaches and were referred to a pediatric psychiatric clinic for psychiatric symptoms from January 2010 to December 2011. All patients completed the CDI and RCMAS. Among them, charts of patients with clinically significant total scores (cutoff>15) for psychiatric symptoms, as defined by the CDI and RCMAS scoring scales, were reviewed. Results: Nineteen patients had headaches and clinically significant total scores for psychiatric symptoms. The mean age at headache diagnosis was 11.7 years, and 57% were male. Mean duration of headache was 11.5 months. Two point eight percent of the patients were diagnosed with psychiatric disorders including major depression (1.7%), generalized anxiety disorder (1.1%), and bipolar disorder (0.1%). Four patients (0.6%) were diagnosed with attention deficit/hyperactivity disorder (ADHD). Total mean CDI and RCMAS scores of patients referred to the psychiatric clinic were 18.8 and 22.2, respectively. There was no correlation between CDI or RCMAS total scores and headache frequency, duration, or severity. Conclusion: We recommend that all patients with headache should be screened for depression and anxiety by CDI and RCMAS scores.