Prostaglandin A₂-induced Apoptosis is Not Inhibited by Heme Oygenase-1 in U2OS Cells

Kyoung-Won Ko(고경원),Sun-Young Lee(이선영),Ji-Hyun Ahn(안지현),Jaetaek Kim(김재택),In-Kyung Kim(김인경),Ho-Shik Kim(김호식) 한국생명과학회 2008 생명과학회지 Vol.18 No.11

Prostaglandin A₂ (PGA₂)는 사람 골육종 세포인 U2OS 세포주에서 apoptosis와 heme oxygenase (HO)-1의 발현을 함께 유도하였다. PGA₂에 의한 apoptosis는 HO-1의 과도한 발현이나 HO-1에 대한 small interfering RNA에 의한 발현저하에 의하여 변동되지 않았으나 H₂O₂에 의한 세포사망은 HO-1의 발현 수준에 반비례하여 변동되었다. 또한 thiol antioxidant인 N-acetyl-L-cysteine (NAC)은 PGA₂에 의한 세포사망과 HO-1의 발현 증가를 모두 차단하였지만, non-thiol antioxidant인 butylated hydroxyanisole (BHA)과 ascorbic acid는 세포사망과 HO-1의 발현 유도를 차단하지 않았다. 이와 같은 결과들은 PGA₂는 산화성 손상에 의해서가 아니라 PGA₂의 thiol-reactivity에 의하여 apoptosis와 HO-1의 발현을 유도하며, HO-1의 발현은 PGA₂에 의한 apoptosis와는 독립적인 현상이거나 기능적으로 apoptosis 유도의 하부에 위치하고 apoptosis의 진행에는 기여하지 않을 것이라는 것을 시사해 준다. Prostaglandin A₂ (PGA₂), one of cyclopentenone PGs, induced both apoptosis and heme oxygenase (HO)-1 expression in U2OS cells. PGA₂-induced apoptosis was not perturbed by either over-expression or knock-down of HO-1, whereas H₂O₂-induced cell death was inversely modulated by the expression level of HO-1. In addition, N-acetyl-L-cysteine (NAC), a thiol antioxidant, blocked both apoptosis and HO-1 expression induced by PGA₂. But, non-thiol antioxidants like butylated hydorxyanisole (BHA) and ascorbic acid did not block either apoptosis or HO-1-induction. Taken together, these results suggest that PGA₂ induces both apoptosis and HO-1 expression, which are critically related to the thiol-reactivity of PGA₂, but not oxidative stress, and HO-1 expression may be independent or functionally located downstream of apoptosis by PGA₂ without contribution to apoptosis progression.

Nutlin-3 induces HO-1 expression by activating JNK in a transcription-independent manner of p53

CHOE, YUN-JEONG,LEE, SUN-YOUNG,KO, KYUNG WON,SHIN, SEOK JOON,KIM, HO-SHIK Spandidos Publications 2014 International journal of oncology Vol.44 No.3

A recent study reported that p53 can induce HO-1 by directly binding to the putative p53 responsive element in the HO-1 promoter. In this study, we report that nutlin-3, a small molecule antagonist of HDM2, induces the transcription of HO-1 in a transcription-independent manner of p53. Nutlin-3 induced HO-1 expression at the level of transcription in human cancer cells such as U2OS and RKO cells. This induction of HO-1 did not occur in SAOS cells in which p53 was mutated and was prevented by knocking down the p53 protein using p53 siRNA transfection, but not by PFT-alpha, an inhibitor of the transcriptional activity of p53. Accompanying HO-1 expression, nutlin-3 stimulated the accumulation of ROS and the phosphorylation of MAPKs such as JNK, p38 MAPK and ERK1/2. Nutlin-3-induced HO-1 expression was suppressed by TEMPO, a ROS scavenger, and chemical inhibitors of JNK and p38 MAPK but not ERK1/2. In addition, nutlin-3-induced phosphorylation of JNK but not p38 MAPK was inhibited by TEMPO. Notably, the levels of nutlin-3-induced ROS were correlated with the mitochondrial translocation of p53 and this induction was prevented by PFT-beta, an inhibitor of the mitochondrial translocation of p53. Consistent with the effect of the ROS scavenger and MAPK inhibitors, PFT-beta reduced HO-1 expression and the phosphorylation of JNK induced by nutlin-3. In the experiments of analyzing cell death, the knockdown of HO-1 augmented nutlin-3-induced apoptosis. Collectively, these results suggest that nutlin-3 induces HO-1 expression via the activation of both JNK which is dependent on ROS generated by p53 translocated to the mitochondria and p38 MAPK which appears to be stimulated by a ROS-independent mechanism, and this HO-1 induction may inhibit nutlin-3-induced apoptosis, constituting a negative feedback loop of p53-induced apoptosis.

Comparison of trophic factors changes in the hippocampal CA1 region between the young and adult gerbil induced by transient cerebral ischemia.

Yan, Bing Chun,Park, Joon Ha,Kim, Sung Koo,Choi, Jung Hoon,Lee, Choong Hyun,Yoo, Ki-Yeon,Kwon, Young-Geun,Kim, Young-Myeong,Kim, Jong-Dai,Won, Moo-Ho Kluwer Academic/Plenum Publishers 2012 Cellular and molecular neurobiology Vol.32 No.8

<P>In the present study, we investigated neuronal death/damage in the gerbil hippocampal CA1 region (CA1) and compared changes in some trophic factors, such as brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF), in the CA1 between the adult and young gerbils after 5 min of transient cerebral ischemia. Most of pyramidal neurons (89%) were damaged 4 days after ischemia-reperfusion (I-R) in the adult; however, in the young, about 59% of pyramidal neurons were damaged 7 days after I-R. The immunoreactivity and levels of BDNF and VEGF, not GDNF, in the CA1 of the normal young were lower than those in the normal adult. Four days after I-R in the adult group, the immunoreactivity and levels of BDNF and VEGF were distinctively decreased, and the immunoreactivity and level of GDNF were increased. However, in the young group, all of their immunoreactivities and levels were much higher than those in the normal young group. From 7 days after I-R, all the immunoreactivities and levels were apparently decreased compared to those of the normal adult and young. In brief, we confirmed our recent finding: more delayed and less neuronal death occurred in the young following I-R, and we newly found that the immunoreactivities of trophic factors, such as BDNF, GDNF, and VEGF, in the stratum pyramidale of the CA1 in the young gerbil were much higher than those in the adult gerbil 4 days after transient cerebral ischemia.</P>

Superconducting MgB2 Wire Drawing Considering Anisotropic Hardening Behavior and Hydrostatic Effect

Young‑Seok Oh,Ho Won Lee,Kook‑Chae Chung,Duck‑Young Hwang,Seong‑Hoon Kang,Jeong Whan Yoon 대한금속·재료학회 2022 METALS AND MATERIALS International Vol.28 No.7

Numerical modeling was conducted to investigate the deformation behavior of powder mixture during multi-pass drawingprocesses for multi-filamentary MgB2wire. A modified Drucker-Prager Cap (DPC) model with an elliptical cap surface usingthe new material characterization method was developed to capture the anisotropic hardening behavior and hydrostatic effectof the powder mixture. A number of uniaxial die compaction, cold isostatic pressing, diametrical compression, and uniaxialcompression tests were conducted using different powder densities to characterize the modified DPC model. A commercialfinite element software ABAQUS with a user subroutine was used to simulate the drawing of the MgB2wire. The densityand area fraction of the powder mixture during the wire-drawing process were verified with experimental results. The differencein packing density at the inner and outer filaments of the MgB2wire was successfully captured by simulation. Inaddition, the effect of the initial packing density on the superconducting properties of MgB2wire was numerically studied. It is shown that the increase in the superconducting area, which results from a high initial packing density, should be moreeffective compared to the increase in the grain connectivity in enhancing the critical current properties for the MgB2wirewhen the final packing density is saturated after a number of drawing processes.

Heme oxygenase-1 (HO-1)/carbon monoxide (CO) axis suppresses RANKL-induced osteoclastic differentiation by inhibiting redox-sensitive NF-κB activation

( Sun-uk Bak ),( Suji Kim ),( Hae-jun Hwang ),( Jung-a Yun ),( Wan-sung Kim ),( Moo-ho Won ),( Ji-yoon Kim ),( Kwon-soo Ha ),( Young-guen Kwon ),( Young-myeong Kim ) 생화학분자생물학회(구 한국생화학분자생물학회) 2017 BMB Reports Vol.50 No.2

Heme oxygenase (HO-1) catalyzes heme to carbon monoxide (CO), biliverdin/bilirubin, and iron and is known to prevent the pathogenesis of several human diseases. We assessed the beneficial effect of heme degradation products on osteoclastogenesis induced by receptor activator of NF-κB ligand (RANKL). Treatment of RAW264.7 cells with CORM-2 (a CO donor) and bilirubin, but not with iron, decreased RANKLinduced osteoclastogenesis, with CORM-2 having a more potent anti-osteogenic effect. CORM-2 also inhibited RANKLinduced osteoclastogenesis and osteoclastic resorption activity in marrow-derived macrophages. Treatment with hemin, a HO-1 inducer, strongly inhibited RANKL-induced osteoclastogenesis in wild-type macrophages, but was ineffective in HO-1^+/-cells. CORM-2 reduced RANKL-induced NFATc1 expression by inhibiting IKK-dependent NF-κB activation and reactive oxygen species production. These results suggest that CO potently inhibits RANKL-induced osteoclastogenesis by inhibiting redox-sensitive NF-κB-mediated NFATc1 expression. Our findings indicate that HO-1/CO can act as an antiresorption agent and reduce bone loss by blocking osteoclast differentiation. [BMB Reports 2017; 50(2): 103-108]

Involvement of Nrf2-Mediated Upregulation of Heme Oxygenase-1 in Mollugin-Induced Growth Inhibition and Apoptosis in Human Oral Cancer Cells

Lee, Young-Man,Auh, Q-Schick,Lee, Deok-Won,Kim, Jun-Yeol,Jung, Ha-Jin,Lee, Seung-Ho,Kim, Eun-Cheol Hindawi Publishing Corporation 2013 BioMed research international Vol.2013 No.-

<P>Although previous studies have shown that mollugin, a bioactive phytochemical isolated from <I>Rubia cordifolia</I> L. (Rubiaceae), exhibits antitumor effects, its biological activity in oral cancer has not been reported. We thus investigated the effects and putative mechanism of apoptosis induced by mollugin in human oral squamous cell carcinoma cells (OSCCs). Results show that mollugin induces cell death in a dose-dependent manner in primary and metastatic OSCCs. Mollugin-induced cell death involved apoptosis, characterized by the appearance of nuclear shrinkage, flow cytometric analysis of sub-G<SUB>1</SUB> phase arrest, and annexin V-FITC and propidium iodide staining. Western blot analysis and RT-PCR revealed that mollugin suppressed activation of NF-<I><I>κ</I></I>B and NF-<I><I>κ</I></I>B-dependent gene products involved in antiapoptosis (Bcl-2 and Bcl-xl), invasion (MMP-9 and ICAM-1), and angiogenesis (FGF-2 and VEGF). Furthermore, mollugin induced the activation of p38, ERK, and JNK and the expression of heme oxygenase-1 (HO-1) and nuclear factor E2–related factor 2 (Nrf2). Mollugin-induced growth inhibition and apoptosis of HO-1 were reversed by an HO-1 inhibitor and Nrf2 siRNA. Collectively, this is the first report to demonstrate the effectiveness of mollugin as a candidate for a chemotherapeutic agent in OSCCs via the upregulation of the HO-1 and Nrf2 pathways and the downregulation of NF-<I><I>κ</I></I>B.</P>

1~2기 본태성 고혈압 환자들에서 Imidapril 대 Enalapril의 항고혈압 효과를 평가하기 위한 무작위, 이중맹검 임상시험

최영진,손대원,김용진,이홍자,채인호,김효수,김철호,오병희,이명묵,박영배,채윤식,이영우 대한순환기학회 1999 Korean Circulation Journal Vol.29 No.11

동종골수이식 후 혈당 및 혈중 지질농도의 변화양상 및 관련인자

이원영,강무일,오은숙,오기원,손현식,윤건호,차봉연,이광우,손호영,강성구,신완식,민우성,김춘주 대한당뇨병학회 2002 Diabetes and Metabolism Journal Vol.24 No.6

연구배경:골수이식은 비교적 젊은 연령의 환자들을 대상으로 하며 면역억제제의 사용기간이 비교적 짧으므로, 주로 고령의 만성 질환 환자에서 시행되는 고형장기이식에서와는 달리 당대사 및 지단백 대사에 있어서 많은 차이점이 있을 것으로 추측된다. 저자들은 전향적 연구를 통하여 골수이식 후 시기별로 혈당 및 혈중지단백 변화 양상을 알아보고 이와 관련된 임상인자들을 규명하고자 하였다. 방법:1998년 10월부터 1999년 8월까지 가톨릭대학교 성모병원에서 동종골수이식을 시행한 환자들 중 43명을 대상으로 이식 전 및 이식 후 1, 2, 3, 4주와 3개월, 6개월에 공복 혈당, 혈중 총 콜레스테롤, 중성지방, 고밀도지단백을 측정하여 골수이식 후 시기별 변화를 관찰하고 여러 임상인자들에 따른 차이를 알아보았다. 결과:1. 공복혈당은 골수이식 수 첫4주 동안 상승하였고 이후 감소하였으나 이식 6개월 시점의 평균 공복혈당은 이식 전보다 유의하게 높게 관찰되었다. 혈중 총 콜레스테롤은 이식 후 1주에 최고치를 형성하였고 이후 기저수준으로 회복되었다가 이식 수 3,6개월에 다시 증가하여 기저치에 비해 유의하게 높았다. 혈중 중성지방은 이식 후 1개월까지 유의하게 증가하였고 이후 감소하여, 3,6개월에는 기저치와 유의한 차이가 관찰되지 않았다. 혈중 고밀도지단백은 이식 후 2,3주에 이식 전보다 유의하게 감소하였고 이후 이식 전 수준으로 회복되었다. 혈중 저밀도지단백은 총 콜레스테롤의 변화와 매우 유사하였다. 2. 골수이식 후 6개월 시점에서 공복 혈당이 126㎎/dL이상인 환자는 7명(16%)이었다. 이들 환자들과 공복혈당 126㎎/dL 미만의 환자 36명을 비교한 결과, 공복혈당이 126㎎/dL 이상인 환자군에서 스테로이드 평균 투여량이 많았고 고밀도지단백이 유의하게 낮았다. 3. 이식편대숙주질환이 발생한 환자는 그렇지 않은 환자보다 이식 후 1, 2, 3주 및 6개월의 총 콜레스테롤이 더 낮았고, 3개월의 공복혈당이 더 높았다. 혈연골수이식 환자군은 비혈연골수이식 환자에 비해 투여된 스테로이드 용량이 더 적음에도 불구하고 이식 후 1, 2, 3주 및 6개월의 총 콜레스테롤 수치가 더 높았다. 스테로이드 고용량 투여군(하루 평균 7.5㎎기준)은 저용량군보다 이식 후 3개월 시점의 공복혈당이 더 높았으나 나머지 시점의 혈당, 혈중 지질농도에 있어서는 유의한 차이가 관찰되지 않았다. 결론:골수이식 후 초기시기에 주로 당 대사 및 지질대사이상이 관찰되며 이는 면역억제제 투여와 관련이 있음을 알 수 있었다. 면역억제제가 고용량 투여되는 합병증 발생 시 이들 대사이상에 관심을 기울여 대처해야 할 것이다. Background: In bone marrow transplantation(BMT), recipients are usually younger and immunosuppressants are open used in shorter period than in solid organ transplantation. Therefore, there might be a difference in glucose and lipid metabolism between BMT and solid organ transplantation. However, the serial changes of metabolic parameters following BMT have not been studied. Therefore, the aim of this study is to investigate the serial changes of blood glucose, lipids and the putative factors that are related with these changes after BMT. Methods: We have prospectively investigated 43 patients who underwent allogeneic BMT. Fasting plasma glucose(FPG), total cholesterol, triglyceride and high-density lipoprotein(HDL) were measured before BMT, and at 1, 2, 3, 4, 12 weeks and 6 months after BMT. The serial changes of these metabolic parameters according to clinical factors including type of BMT, mean daily steroid dosage, and occurrence of graft versus host disease (GVHD) were examined. Results: 1. Mean FPG level increased during 4 weeks after BMT and remained above basal value at post-transplant 6 months. Total Cholesterol level was increased during initial 4 weeks after BMT and was above basal value at post-BMT of 3 and 6 months. Triglyceride level was progressively increased during initial 4 weeks after BMT, but returned to basal value there after. HDL-cholesterol level was significantly decreased during initial 4 weeks after BMT, but returned to basal value there after. 2. Patients with FPG above 126 mg/dL and the other patients, the former received larger amounts of daily steroid and had lower HDL-cholesterol level. 3. The changes of metabolic parameters were different according to type of BMT, steroid dose, and occurrence of GVHD. Conclusion: Although there was increase of FPG, TC, TG and decrease of HDL-C during initial 4 weeks after BMT, these metabolic changes recovered slowly thereafter. Immunosuppressants are thought to be associated with these changes. Further observation will be needed for the long-term effect of BMT on metabolic changes(J Kor Diabetes Asso 24:689~698, 2000).

十二變에 대한 考察 : 六元正紀大論을 중심으로

채영진,남호현,이석모,여성원,한성규,이재원,안민식,정헌영,금경수 한국전통의학연구소 2003 한국전통의학지 Vol.13 No.1

The six kinds of natural factors(It refers to wind, cold, summer-heat, dampness, dryness and fire.) is constantly moving to maintain the balance of whole climate of one year. Four seasons are the largest mediation of whole climate of one year. The cold and the heat have the relationship of mutual intervention. The dampness and the dryness have it also. In this process they raise various climate appearance. And that various climate appearance influence the whole lives on the earth. This paper is concerned with the classification of them.

동일한 환자에서 조혈모세포이식 전후의 호중구감소 기간 중 감염양상에 대한 비교연구 : 중심정맥관 관련 패혈증을 중심으로 Based on Central Venous Catheter Related Septicemia

류재호,노규태,이영석,이영호,권혁찬,김재석,김효진,이영민,박혜원,박근희 대한조혈모세포이식학회 2002 대한조혈모세포이식학회지 Vol.7 No.1

연구배경: 동일한 환자를 대상으로 조혈모세포이식 전 일반 병실에서의 관해유도 항암제치료 및 강화요법으로 인한 호중구감소 기간의 감염양상과 고용량 항암제치료 후 무균실에서의 조혈모세포이식 시 호중구감소 기간의 감염양상을 중심정맥관 관련 패혈증을 중심으로 비교 연구함으로써 효율적인 감염관리지침을 마련하고자 하였다. 대상 및 방법: 1999년 1월부터 2001년 7월까지 2년 7개월간 동아대학교병원 일반병실에서 악성혈액질환으로 항암제 치료를 받다가 조혈모세포이식을 시행받았던 22명을 대상으로 중심정맥관 관련 패혈증의 형태를 비교분석하였다. 결과: 대상 환자들의 일반병실과 무균실에서의 입원기간은 각각 32±13일, 33±19일, 호중구 감소기간은 15±12일, 17±18일, 호중구 감소기간의 발열 횟수는 14회, 14회로서 입원병실의 종류에 따른 차이는 없었다. 환자들의 중심정맥관 사용일수는 일반병실에서 29일(7~545일), 무균실에서 100.5일(25~606일)이었으며, 총 사용일수는 각각 1,515일, 3,250일로서 무균실에서의 중심정맥관 사용일수가 의미 있게 길었다(P=0.001). 중심정맥관 사용 일수에 대한 감염률은 각각 5.28/1,000일, 3.08/1,000일로서 일반병실에서 그 빈도가 높았으나 통계적 유의성은 보이지 않았다(P=0.141). 결론: 중심정맥관 삽입 후 일반병실에서 항암제 치료를 받던 환자가 조혈모세포이식을 위하여 무균실에 입원하는 경우, 중심정맥관을 교체하는 것이 감염관리를 위하여 바람직할 것으로 생각된다. Background: We compared the incidence of central venous catheter (CVC) related septicemia during neutropenic period in the same patient, which developed following chemotherapy for remission induction and consolidation, or hematopoietic stem cell transplantation (HSCT). Methods: We retrospectively reviewed the medical records and laboratory data of 22 patients with hematologic malignancies who received anticancer chemotherapy followed by HSCT at Dong-A University Hospital between January, 1999 and July, 2001. We investigated the duration of hospitalization, duration of neutropenic period, duration of catheterization, microbiologically documented organisms and incidence of CVC related septicemia. Results: The data in general ward (before HSCT) and laminar air flow room (after HSCT) were as follows: duration of hospitalization was 32±13 days and 33±19 days, duration of neutropenic period was 15±12 days and 17±18 days, median duration of catheterization was 29 days (7~545 days) and 100.5 days (25~606 days) (P=0.001), and incidence of CVC related septicemia was 5.28/1000 days and 3.08/1000 days, respectively. In the CVC related septicemia, the most common etiologic organism was coagulase negative staphylococcus. Conclusion: We suggest that the exchange of CVC before admission to laminar air flow room could decrease the incidence of CVC related septicemia in HSCT recipients.