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.

PGA2-induced expression of HO-1 is mediated by transcriptional upregulation of Nrf2

Sang-sun Lee,Yun-Jeong Choe,Hyein Lee,Sun-Young Lee,Ho-Shik Kim 대한독성 유전단백체 학회 2019 Molecular & cellular toxicology Vol.15 No.2

Backgrounds: Prostaglandin (PG) A2 reportedly stimulated expression of heme oxygenase (HO)-1 at the level of transcription via the activation of p38MAPK. Details of the mechanism, however, have not been provided, and this includes identification of the transcription factors responsible for PGA2-induced HO-1 expression. Herein is described an analysis of the role of nuclear factor erythroid 2 related factor 2 (Nrf2) and how PGA2 increases the activity of Nrf2 during PGA2-induced HO-1 expression. Methods: Expressions of HO-1 and Nrf2 were analyzed at the levels of both mRNA and protein. Nrf2 siRNA, SB203580, an inhibitor of p38MAPK, and scavengers of reactive oxygen species (ROS) were used to identify the effects of Nrf2, p38MAPK and ROS on PGA2-induced HO-1 expression. Results: Although SB203580 suppressed PGA2-induced HO-1 expression, genetic activation of p38MAPK could not stimulate the transcription of HO-1. Cycloheximide (CHX), an inhibitor of protein translation, almost completely prevented PGA2-induced increase of HO-1 transcription, but it did not prevent the phosphorylation of p38MAPK, which suggests that both de novo protein synthesis and p38MAPK activity are required to induce the transcription of HO-1 in response to PGA2 treatment. In addition, PGA2 increased the level of both Nrf2 mRNA and protein in a dose-dependent manner. Knockdown of Nrf2 using small interfering RNA (siRNA) suppressed PGA2-induced HO-1 expression. The PGA2-induced transcription of Nrf2 was prevented by ROS scavengers such as n-acetyl-l-cysteine and tempol but not CHX. Furthermore, siRNA against p38MAPK did not change the level of nuclear Nrf2 protein. Conclusion: These findings suggest that PGA2 induces HO-1 transcription via an increase in Nrf2 protein, the transcription of which is initiated by an accumulation of ROS that is independent of the p38MAPK activation pathway.

교류분석 이론에 근거한 드라이버와 시간구조화 척도 타당성 연구 : Study on the Validation of Driver Scale and Time Structuring Scale

문호영(Ho Young, Moon),윤영진(Young Jin, Yun) 한국교류분석상담학회 2021 교류분석상담연구 Vol.11 No.1

본 연구의 목적은 교류분석 이론에 근거한 성인용 드라이버와 시간구조화 척도를 개발하고 타당성을 검증하는 것이다. 연구 대상은 성인 1,671명(남 594명, 여 1,067명)으로 1차(2018년)와 2차(2019년) 두 차례의 연구로 진행되었다. 1차 연구는 드라이버 척도 64문항(완벽하게 하라 12문항, 남을 기쁘게 하라 12문항, 서둘러라 12문항, 열심히 하라 14문항, 강해져라 14문항), 시간구조화 척도 71문항(폐쇄 14문항, 의식 14문항, 활동 10문항, 잡담 13문항, 게임 10문항, 친밀 10)에 대해 타당성을 검증하여 신뢰로운 문항을 선정하는 것이었다. 2차 연구는 1차 연구분석 결과 선정된 드라이버 척도 45문항(5요인 각 9문항), 시간구조화 척도 48문항(6요인 각 8문항)에 대한 타당성 검증과정을 거쳐 드라이버와 시간구조화 척도를 표준화하는 것이었다. 연구 결과를 보면, 개발된 드라이버 45문항과 시간구조화 48문항 모두 신뢰롭고 타당도가 높은 문항임이 확인되었다. 본 연구에서 개발된 두 척도는 급속한 성장을 이룬 한국사회 성인의 병리적 현상과 특성을 이해하는데 유용할 것으로 판단된다. 또한 드라이버와 시간구조화 척도는 심리특성 진단, 학교 교육, 기업 등 다양한 분야에서 진단도구로 활용될 수 있다는 점에서 그 의의가 있다고 할 수 있다. The purpose of this study is re-validate the validation of the Driver Scale and Time Structuring Scale devised by Moon, ho- young in 2017. This study is carried out two times with 1671 people - 1021 adults at first time and 650 at the other. The first study included 50 questions on driver scale devised by Moon, ho- young and 64 questions that added 14 questions: two questions on ‘Be perfect’, two on ‘Please others’, two on ‘Hurry up’, four on ‘Try hard’, four on ‘Be strong.’71 questions regarding on time structuring scale were studied in detail as the following: 11 questions were added to the 60 basic questions and the 11 questions were consisted of four questions on ‘Withdrawal’, four on ‘Rituals’, and three questions on ‘Pastimes’. The writers select highly valid and trustworthy questions using various method of analysis. The second study was conducted to validate the validation of the scale with 45 questions on drive scale and 48 questions on time structuring scale that were chosen from the first study result. Through these two studies researchers completed the Korean driver scale and time structuring scale. The result of this study clearly shows that 45 questions on driver scale questions and 48 questions on time structuring scale devised by Moon, ho- young(2017) including some modified questions and one newly invented question were highly valid and trustworthy in evaluating the validity of each scale. This result of this study proves that the driver scale and time structuring scale devised by Moon, ho-young(2017) is a valid tool for testing Korean adults.

PGA2 induces the expression of HO-1 by activating p53 in HCT116 cells

Hyein Lee,Sang-Sun Lee,Ji-Young Park,Yun-Jeong Choe,이선영,Ho-Shik Kim,H.-S. Kim 대한독성 유전단백체 학회 2017 Molecular & cellular toxicology Vol.13 No.2

Prostaglandin (PG) A2 which is a cytotoxic PG, was reported to induce the expression of heme oxygenase (HO)-1 via activation of p38MAPK to keep U2OS cells from cell cycle arrest in G2M phase. The expression of HO-1 is primarily regulated at the level of transcription. But the transcription factors that are responsible for PGA2-induced HO-1 expression were not clarified yet. Here, we report that PGA2-induced transcription of HO-1 is mediated by p53, a tumor suppressive transcription factor. In HCT116 cells, PGA2 treatment led to the phosphorylation of p53 and an increase of p21WAF1 transcription as well as the activation of HO-1 transcription. Knocking p53 down via RNA interference or inhibiting the p53’s transcriptional activity by pifithrin-α treatment led to suppression of the increase in the level of both HO-1 expression and activity of HO-1 promoter. Pretreatment of NU- 7441, a chemical inhibitor of DNA-activated protein kinase (DNA-PK), prevented both the PGA2-induced phosphorylation of p53 and an increase of HO-1 transcription. In addition, N-acetyl-l-cysteine, a scavenger of reactive oxygen species (ROS), also mimicked the effect of NU-7441 on the PGA2-induced activation of p53 and HO-1 transcription. Collectively, these results suggest that PGA2 induces the expression of HO-1 via activation of p53, which is mediated by the ROSDNA- PK pathway.

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]

Carbon monoxide prevents TNF-α-induced eNOS downregulation by inhibiting NF-κB-responsive miR-155-5p biogenesis

Choi, Seunghwan,Kim, Joohwan,Kim, Ji-Hee,Lee, Dong-Keon,Park, Wonjin,Park, Minsik,Kim, Suji,Hwang, Jong Yun,Won, Moo-Ho,Choi, Yoon Kyung,Ryoo, Sungwoo,Ha, Kwon-Soo,Kwon, Young-Guen,Kim, Young-Myeong Nature Publishing Group 2017 Experimental and molecular medicine Vol.49 No.11

<P>Heme oxygenase-1-derived carbon monoxide prevents inflammatory vascular disorders. To date, there is no clear evidence that HO-1/CO prevents endothelial dysfunction associated with the downregulation of endothelial NO synthesis in human endothelial cells stimulated with TNF-α. Here, we found that the CO-releasing compound CORM-2 prevented TNF-α-mediated decreases in eNOS expression and NO/cGMP production, without affecting eNOS promoter activity, by maintaining the functional activity of the <I>eNOS</I> mRNA 3′-untranslated region. By contrast, CORM-2 inhibited MIR155HG expression and miR-155-5p biogenesis in TNF-α-stimulated endothelial cells, resulting in recovery of the 3′-UTR activity of <I>eNOS</I> mRNA, a target of miR-155-5p. The beneficial effect of CORM-2 was blocked by an NF-κB inhibitor, a miR-155-5p mimic, a HO-1 inhibitor and siRNA against HO-1, indicating that CO rescues TNF-α-induced eNOS downregulation through NF-κB-responsive miR-155-5p expression via HO-1 induction; similar protective effects of ectopic HO-1 expression and bilirubin were observed in endothelial cells treated with TNF-α. Moreover, heme degradation products, except iron and <I>N</I>-acetylcysteine prevented H<SUB>2</SUB>O<SUB>2</SUB>-mediated miR-155-5p biogenesis and eNOS downregulation. These data demonstrate that CO prevents TNF-α-mediated eNOS downregulation by inhibiting redox-sensitive miR-155-5p biogenesis through a positive forward circuit between CO and HO-1 induction. This circuit may play an important preventive role in inflammatory endothelial dysfunction associated with human vascular diseases.</P>

Effect of DREAMMO<SUP>®</SUP> Scalp Lotion on Hair Growth Promotion in an Alopecia Model of C57BL/6 Mice

Seung Ho Lee,Hwa Jeung Lee,In Jeoung Baek,Jung Min Yon,Sang Yoon Nam,Beom Jun Lee,Young Won Yun,Yun-Bae Kim,Seock Yeon Hwang,Jin Tae Hong 한국실험동물학회 2006 Laboratory Animal Research Vol.22 No.1

Scalp hair loss has increased recently in young-aged people as well as middle-aged people, and although there are no serious in health problems, scalp hair loss may significantly affect a variety of psychological and social experiences and the individual's quality of life. DREAMMO scalp lotion is composed of several plant extracts which are known to be used as oriental medicine to prevent hair loss or promote hair growth in alopecia. This study was carried out to investigate the effect of DREAMMO scalp lotion on hair growth in an alopecia model of C57BL/6 mice. Mice were divided into three experimental groups including control, DREAMMO scalp lotion and 3% Minoxidil (MXD). The test compounds were topically treated with 0.2 ㎖ per mouse per day for 4 weeks. The hair growth was determined photographically and histologically in an alopecia model of C57BL/6 mice. After 3-4 weeks, DREAMMO scalp lotion significantly increased hair growth compared to the controls in the dorsal skin of C57BL/6 mice. DREAMMO scalp lotion also promoted the elongation of hair follicles than the controls. These results suggest that DREAMMO scalp lotion has a hair growth activity and can be useful for the treatment of alopecia.

터널 변위 거동 및 수치 모의실험의 결합 해석

정윤영 ( Yun Young Jeong ),한희수 ( Heui Soo Han ),이재호 ( Jae Ho Lee ) 대한지질공학회 2010 지질공학 Vol.20 No.1

이 연구는 터널설계의 안정성을 예측하기 위한 터널거동분석에 초점을 맞춘 것이다. 3차원 수치해석, 현장계측 후 최대변형 및 사쿠라이에 의해 제안된 터널변형에 관한 경험적 안정성 평가방법들을 결합한 평가기법을 사용하였다. 사쿠라이가 사용한 계측자료들은 새로운 해석기법을 도입하여 재해석되었다. 터널안정해석을 위한 사쿠라이의 경험적 추세선은 이론적 추세선으로 새로이 도입되었으며, 이는 안정, 불안정 및 파괴영역으로 구분되었다. 터널 현장자료의 새 해석기법을 평가하기 위한 현장의 적용 예로, 김포의 지하철 9호선으로 연결되는 인천공항의 지하철터널을 이용하였다. 그 결과 터널보강후 인천공항 지하철의 상부 및 하부터널 모두 충분한 안정성을 보였다. 마이크로 실리카 그라우팅과 엄브레라방법에 의한 지반보강 후 겉보기 영계수가 상당히 증가하는 것을 볼 수 있었다. 그러므로, 제안된 새 해석기법을 이용하면, 터널변형과 지반조건에 따른 최적의 보강기법 선정에 활용할 수 있다. This study is focused on the analysis of tunnel behavior to estimate the stability on tunnel design. An estimation method was proposed as a hybrid consideration, which contains the displacement analysis by 3D numerical simulation, the maximum displacement obtained after field measurement, and an assessment of tunnel stability using a deformation analysis proposed by Sakurai(1988, 1997). The points of case study by Sakurai(1988, 1997) were replotted considering his analysis. From the new analysis of the tunnel case study, the trend line for analyzed points is analogized, which curve is divided into stable, unstable and failure zone. To evaluate the estimation method, a special shape of railway tunnel was selected, which are the Inchon international airport rail way connected to subway line 9 in Gimpo, Korea. The point s of upper and below track on the Inchon international airport rail way were satisfied to the stability of tunnel after reinforcing. Also the points shows the higher apparent Young`s modulus, which resulted from improvement on shear strength by the micro silica grouting and the supporting of umbrella method. Therefore, if new analysis used, proper tunnel reinforcing method could be selected according to tunnel strain and geological property.

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

크론병에 대한 CoPPLX의 방어효과에 대한 연구

이호학,김유림,문창기,이재일,양병윤,김종수,이정민,정재혁,안석진,박상준,김윤권,김소연,김영중,조민구,최영자,장성조 圓光大學校 醫科學硏究所 2005 圓光醫科學 Vol.20 No.1