PGA2-induced HO-1 attenuates G2M arrest by modulating GADD45α expression

Yun-Jeong Choe,고경원,Hyein Lee,이선영,Byung-Chul Kim,Ho-Shik Kim,Ho-Shik Kim 대한독성 유전단백체 학회 2015 Molecular & cellular toxicology Vol.11 No.4

Prostaglandin (PG) A2, a cyclopentenone PG, arrested the growth of U2OS cells in the G2M phase. While inducing G2M arrest, PGA2 increased the expression of heme oxygenase-1 (HO-1) at the level of transcription along with the accumulation of ROS and the activation of MAPKs including JNK, p38MAPK, and ERK1/2. Among the MAPKs, the inhibition of p38MAPK by a specific chemical inhibitor SB203580, or by RNA interference, but not JNK or ERK1/2, attenuated the PGA2-induced transcription of HO-1. Nacetylcysteine (NAC), a ROS scavenger, prevented PGA2-induced G2M arrest, p38MAPK activation and transcriptional induction of HO-1. PGA2 also stimulated GADD45α expression at the level of transcription, and the knockdown of GADD45α repressed PGA2- induced G2M arrest. Finally, the knockdown of the HO-1 protein elevated PGA2-induced GADD45α expression as well as G2M arrest. Collectively, these results suggest that PGA2 causes an increase in ROS accumulation which initiates both HO-1 transcription via p38MAPK, and G2M arrest via GADD45α transcription, and HO-1 attenuates G2M arrest by modulating the expression of GADD45α.

Hypoxia-Responsive MicroRNA-101 Promotes Angiogenesis <i>via</i> Heme Oxygenase-1/Vascular Endothelial Growth Factor Axis by Targeting Cullin 3

Kim, Ji-Hee,Lee, Kwang-Soon,Lee, Dong-Keon,Kim, Joohwan,Kwak, Su-Nam,Ha, Kwon-Soo,Choe, Jongseon,Won, Moo-Ho,Cho, Byung-Ryul,Jeoung, Dooil,Lee, Hansoo,Kwon, Young-Guen,Kim, Young-Myeong Mary Ann Liebert 2014 Antioxidants & redox signaling Vol.21 No.18

<P>Aims: Hypoxia induces expression of various genes and microRNAs (miRs) that regulate angiogenesis and vascular function. In this study, we investigated a new functional role of new hypoxia-responsive miR-101 in angiogenesis and its underlying mechanism for regulating heme oxygenase-1 (HO-1) and vascular endothelial growth factor (VEGF) expression. Results: We found that hypoxia induced miR-101, which binds to the 3 ' untranslated region of cullin 3 (Cul3) and stabilizes nuclear factor erythroid-derived 2-related factor 2 (Nrf2) via inhibition of the proteasomal degradation pathway. miR-101 overexpression promoted Nrf2 nuclear accumulation, which was accompanied with increases in HO-1 induction, VEGF expression, and endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) production. The elevated NO-induced S-nitrosylation of Kelch-like ECH-associated protein 1 and subsequent induction of Nrf2-dependent HO-1 lead to further elevation of VEGF production via a positive feedback loop between the Nrf2/HO-1 and VEGF/eNOS axes. Moreover, miR-101 promoted angiogenic signals and angiogenesis both in vitro and in vivo, and these events were attenuated by inhibiting the biological activity of HO-1, VEGF, or eNOS. Moreover, these effects were also observed in aortic rings from HO-1(+/-) and eNOS(-/-) mice. Local overexpression of miR-101 improved therapeutic angiogenesis and perfusion recovery in the ischemic mouse hindlimb, whereas antagomiR-101 diminished regional blood flow. Innovation: Hypoxia-responsive miR-101 stimulates angiogenesis by activating the HO-1/VEGF/eNOS axis via Cul3 targeting. Thus, miR-101 is a novel angiomir. Conclusion: Our results provide new mechanistic insights into a functional role of miR-101 as a potential therapeutic target in angiogenesis and vascular remodeling. Antioxid. Redox Signal. 21, 2469-2482.</P>

담도 폐쇄증 환아의 간경변 조직에서 유전자 발현의 변동

최병호,이현미,김문규,김정철 경북대학교 병원 2002 경북대학교병원의학연구소논문집 Vol.6 No.1

목적:간외 담도 폐쇄증은 소아영역에서 간이식의 적응증으로 가장 많은 부분을 차지하는 질환으로 서 발생원인은 아직 밝혀져 있지 않으며, 간외 담도의 진행성 소실을 설명하기 위한 많은 가설이 제시되어 있으나 증명되지 않았다.따라서 담도 폐쇄증의 원인과 발생과정을 이해하고 조기 진단을 위해 발생과 진행,간섬유화 등에 관여하는 가능한 유전자의 규명은 매우 의미있는 시도이다. 방법:인간 모유두 새포로부터 구축한 cDNA ilbrary를 이용하여 dot blot panel을 제작하였다. 생체부분 간이식 수술시 환아가 간경변 조직과 공여자의 정상 간조직을 얻은 후 각각의 조직으로부터 RNA를 분리한 후 역전사하여 cDNA를 얻었다.rendom primed DNA labelling방법을 이용하여 방사능 동위원소를 붙임으로써 방사능 표지된 cDNA probe를 만들었다.membrane을 30분간 prehybridization 시킨 후 1시간 동안 hybridization 시켰다.reverse dot hybridization 결과 담도 폐쇄성 간경변 조직과 정상 간 조직에서 차이나는 클론을 확인하고 해당 클론의 핵산 염기서열을 분석하였다.그 결과를 BLAST를 이용하여 GenBank의 database와 비교 검색함으로써 선택된 클론이 기존의 어느 유전자와 상동성을 가지는지 확인하였다. 결과:담도 폐쇄성 간경병 조직에서 발현이 증가한 유전자는 26종으로서 bcl-w,laminin binding protein, hepatocyte growth factor-regulated tyrosine kinase substrate(HRS), tymosin β-4,10,transforming growth factor(TGF)-β, tissue inhibitor of metalloproteinase(TIMP)-1,signal recognition particle(SRP)4, eukaryotic initiation factor(eIF)-2 α kinase,lysyl oxidase, aldolase A, γ-glutamylcystein synthetase,collagen typeⅠ α1,2,collagen typeⅢ, fibronectin, osteonetin, insulin-like growth factor binding protein(IGFBP)2,3 등이었다.담도 폐쇄성 간경변 조직에서 발현이 감소한 유전자는 gastrula zinc finger protein과 novel gene:K0059 이었다. 결론:이 연구는 담도 폐쇄증과 간섬유화의 특이유전자 규명으로 담도 폐쇄증과 간섬유화의 원인규명에 기여하고 질환의 조기 발견과 간경화의 치료와 예방 물질의 개발을 위한 기초 자료가 될 것으로 생각한다. Purpose: Extrahepatic biliary atresia is the most common indication for liver transplantation in children. Serveral studies have been explain the destructive, inflammatory process leading to fibrosis and obliteration of the biliary tract, but the etiology of this disorders remains unknown. It would be very significant to identify genes that are specifically expressed in pathologic liver tissue of biliary atresia and analyze the pattern of expression in those genes. Method: We made dot blot panels consisting of 1,730 different EST(expressed sequence tags) clones which were isolated from human hair dermal papilla cell cDNA library.Liver tissues were taken from a recipient with biliary atresia and a normal donor during living-related liver transplantation.Total RNA was extracted from each sample and reversely transcribed to make cDNA. Then radioablelled cDNA probe pools were made by random primed DNA labeing method and used for screening differentially expressed genes using EST dot blot panel. Results: Among the total of 1,730 EST clones, 26 cDNA clones were overexpressed in biliary cirrhosis.They revealed homology to genes encoding bcl-w, laminin binding protein, hepatocyte growth factor-regulatef tyrosine kinase substrate(HRS),thymosin β-4, 10; transforming growth factor(TGF)-β, tissue inhibitor of metalloproteinase(TIMP)-1, signal recognition particle(SRP)4, eukaryotic initiation factor(eIF)-2αkinase, lysyl oxidase, aldoase A, γ-glutamylcystein synthetase, collagen typeⅠα1,2,collagen typeⅢ,fibronectin,osteonectin,insulin-like growth factor binding protein(IGFBP)-2,3,and more. In addition, the expression of 2 clones ahowed that gastrula zinc finger protein and one novel gene were decreased in biliary atresia. Conclusions: This study identified differential EST screening technique.We believe this studt could lead to a better understanding of the pathogenesis of biliary atresia and hepatic fibrosis.(J Korean Pediatr Soc 1999;42:1-10)

AC4C계 Al합금에서 미세조직에 미치는 중력주조와 가압주조의 영향에 관하여

이병호,김정욱,최진일 단국대학교 신소재기술연구소 2000 신소재 Vol.9 No.-

자동차용 Pump/housing에 사용되는 AC4C계 A1합금을 중력주조와 가압주조방법으로 응고시킬 때 가스기공, 수축결함과 같은 미세조직의 거동과 기계적 성질의 변화를 조사하였다. 압력의 증가에 기인한 빠른 응고속도는 미세수축공과 기공의 결함을 감소시켜 결정조직의 미세화를 일으켰다. 중력주조재는 주괴면 부근에 역편석을 일으켰으나 가압재는 응고시간에 감속에 기인하여 center방향으로 합금성분의 정상적인 편석이 나타났다. It was investigated in the behavior of microstructure such as gas porosity, shrinkage defect and mechanical properties during solidification of AC4C alloy for use of Pump/housing. Crystal structure of squeeze cast was fine and dense, because of the greater solidification rate of cast material resulting from the applied pressure. A normal segregation phenomena of an increasing in amount of eutectic towards the center of the specimen was observed for squeeze casting

N-13 암모니아 PET 동적영상과 인자분석을 이용한 심근 혈류량 정량화

김준영,이경한,최용,김종호,김상은,최연성,임기천,김병태,우상근 대한핵의학회 1999 핵의학 분자영상 Vol.33 No.3

Purpose: We evaluated the feasibility of extracting pure left ventricular blood pool and myocardial time-activity curves (TACs) and of generating factor images from human dynamic N-13 ammonia PET using factor analysis. The myocardial blood flow (MBF) estimates obtained with factor analysis were compared with those obtained with the user drawn region-of-interest (ROI) method. Materials and Methods: Stress and rest N-13 ammonia cardiac PET imaging was acquired for 23 min in 5 patients with coronary artery disease using GE Advance tomograph. Factor analysis generated physiological TACs and factor images using the normalized TACs from each dixel. Four steps were involved in this algorithm: (a) data preprocessing; (b) principal component analysis; (c) oblique rotation with positivity constraints; (d) factor image computation. Area under curves and MBF estimated using the two compartment N-13 ammonia model were used to validate the accuracy of the factor analysis generated physiological TACs. The MBF estimated by factor analysis was compared to the values estimated by using the ROI method. Results: MBF values obtained by factor analysis were linearly correlated with MBF obtained by the ROI method (slope=0.84, r=0.91). Left ventricular blood pool TACs obtained by the two methods agreed well (Area under curve ratio: 1.02 (0∼1 min), 0.98 (0∼2 min), 0.86 (1∼2 min)). Conclusion: The results of this study demonstrates that MBF can be measured accurately and noninvasively with dynamic N-13 ammonia PET imaging and factor analysis. This method is simple and accurate, and can measure MBF without blood sampling, ROI definition or spillover correction.

EDITORIAL : A disappearing vertical infection: will hepatitis B be a forgotten disease in children?

( Byung Ho Choe ) 대한내과학회 2014 The Korean Journal of Internal Medicine Vol.29 No.3

The major transmission route of hepatitisB virus (HBV) is perinatal, especiallyduring delivery in endemic areas. To decrease the prevalence of and complicationsassociated with chronic hepatitisB, universal vaccination and maternalscreening for hepatitis B serumantigen (HBsAg) are essential. Almost5% of newborn infants are inadequatelyprotected by current immunoprophylacticmeasures, and this figure mayrise to 50% if prophylaxis is poor or thematernal HBV DNA load is high (> 107IU/mL) [1].

Safety and Competency are the Main Priorities in Pediatric Endoscopy

Byung-Ho Choe 대한소화기내시경학회 2020 Clinical Endoscopy Vol.53 No.4

COMMENTARY

The Escape of Temperature-Sensitive T Antigen Immortalized Rat Hepatocytes from Conditional Immortalization

Kim, Byung-Ho,Han, Yo Seb,Choe, Bong-Keun,Cho, Hyeseong,Nam, Gi Deog,Lee, Jin Woo,Kim, Young Il,Park, Jai Kyung,Dong, Seok Ho,Kim, Hyo Jong,Chang, Young Woon,Lee, Joung Il,Chang, Rin Cognizant Communication Corp. 2005 CELL TRANSPLANTATION Vol.14 No.7

<P>Conditionally immortalized hepatocytes (CIH) established with a gene for the temperature-sensitive mutant of the T antigen (tsT) have characteristics to stop proliferating and to differentiate at nonpermissive temperatures (37-39 degrees C) due to inactivation of the T antigen. Therefore, they may be a good alternative to primary hepatocytes for experimental investigations or clinical applications. Deinduction of the T antigen results in a transient increase of p53 in these cells, leading to reexpression of normal senescence because of the telomere attrition occurring during the early stages of immortalization. To determine this T antigen dependency for the maintenance of immortality, a type of rat CIH was cultured continuously at 39 degrees C. The frequency of occurrence of T-antigen-independent clones ranged from 0.053% to 0.093%. These clones maintained the temperature-sensitive property of the T antigen; nevertheless, they were able to progress to the S phase and proliferate without undergoing apoptosis at 39 degrees C as at 33 degrees C, a permissive temperature. The temperature-sensitive point mutation of tsT was not affected in these clones and the T antigen was functioning properly. The integrity of the p53 pathway was also maintained from the point of Western blot analysis of p21. Although the telomerase continued to be expressed and the telomere length was maintained, marked chromosomal damage could not be avoided in these cells. It is a plausible explanation that this escape phenomenon from conditional immortalization may be related to the change of other genes involved in cell cycles, which have yet to be elucidated. In conclusion, CIH could lose their temperature-sensitive characteristics without the change of tsT, itself, and the T antigen is not always necessary to maintain their immortality. Therefore, the results obtained from experimental investigations using these cells should be interpreted carefully, and unpredictable phenotypic changes should also be taken into consideration when using them in clinical applications.</P>

The Escape of Temperature-Sensitive T Antigen Immortalized Rat Hepatocytes From Conditional Immortalization

Kim, Byung-Ho,Han, Yo Seb,Choe, Bong-Keun,Cho, Hyeseong,Nam, Gi Deog,Lee, Jin Woo,Kim, Young Il,Park, Jai Kyung,Dong, Seok Ho,Kim, Hyo Jong,Chang, Young-Woon,Lee, Joung-Il,Rin Chang KYUNG HEE UNIVERSITY MEDICAL CENTER 2006 고황의학상 수상논문집 Vol.21-22 No.-

Conditionally immortalized hepatocytes (CIH) established with a gene for the temperature-sensitive mutant of the T antigen (tsT) have characteristics to stop proliferating and to differentiate at nonpermissive temperatures (37-39℃) due to inactivation of the T antigen. Therefore, they may be a good alternative to primary hepatocytes for experimental investigations or clinical applications. Deinduction of the T antigen results in a transient increase of p53 in these cells, leading to reexpression of normal senescence because of the telomere attrition occurring during the early stages of immortalization. To determine this T antigen dependency for the maintenance of immortality, a type of rat CIH was cultured continuously at 39℃. The frequency of occurrence of T-antigen-independent clones ranged from 0.053% to 0.093%. These clones maintained the temperature-sensitive property of the T antigen; nevertheless, they were able to progress to the S phase and proliferate without undergoing apoptosis at 39℃ as at 33℃, a permissive temperature. The temperature-sensitive point mutation of tsT was not affected in these clones and the T antigen was functioning properly. The integrity of the p53 pathway was also maintained from the point of Western blot analysis of p21. Although the telomerase continued to be expressed and the telomere length was maintained, marked chromosomal damage could not be avoided in these cells. It is a plausible explanation that this escape phenomenon from conditional immortalization may be related to the change of other genes involved in cell cycles, which have yet to be elucidated. In conclusion, CIH could lose their temperature-sensitive characteristics without the change of tsT, itself, and the T antigen is not always necessary to maintain their immortality. Therefore, the results obtained from experimental investigations using these cells should be interpreted carefully, and unpredictable phenotypic changes should also be taken into consideration when using them in clinical applications.

오디 괄약근 기능 이상으로 인한 소아의 재발 급성 췌장염 1예

최병호,박선민,김호각,김정미,홍석진,김정옥,조민현,최병호,Choi, Byung-Ho,Park, Sun-Min,Kim, Ho-Gak,Kim, Jung-Mi,Hong, Suk-Jin,Kim, Jung-Ok,Cho, Min-Hyun,Choe, Byung-Ho 대한소아소화기영양학회 2008 Pediatric gastroenterology, hepatology & nutrition Vol.11 No.2

저자 등은 원인이 확실하지 않았던 재발성 급성 췌장염의 14세 소아 환자에서 오디 괄약근 운동 검사로 오디 괄약근 운동 이상을 진단하고, 내시경 췌관 유두 괄약근 절개술을 시행하여 치료한 증례를 경험하였기에 보고한다. Recent studies suggest that sphincter of Oddi dysfunction (SOD) is one of the possible causes of unexplained recurrent acute pancreatitis in children. A 14-year-old boy who had suffered from idiopathic recurrent acute pancreatitis was diagnosed with SOD. Abdominal ultrasonography, computerized tomography, and magnetic resonance cholangiopancreatography revealed no evidence of stone, tumor, or pancreatic ductal anomaly. Endoscopic retrograde cholangiopancreatography (ERCP) and sphincter of Oddi manometry (SOM) revealed elevated basal pressure and tachyoddia consistent with SOD. Hence, an endoscopic pancreatic sphincterotomy was performed. We report a case of recurrent acute pancreatitis associated with SOD in a child. ERCP and SOM may be considered in patients with multiple unexplained attacks of pancreatic pain and negative abdominal imaging.