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.

Dimethylnitrosamine 유발 급성 간 손상 흰쥐에서 ^(99m)Tc-Lactosylated Serum Albumin을 이용한 간 기능의 평가

정신영,이재태,서명랑,유정아,배진호,안병철,황재석,정재민,하정희,이규보 대한핵의학회 2003 핵의학 분자영상 Vol.37 No.6

목적: ^(99m)Tc-lactosylated serum albumin (^(99m)Tc-LSA)은 간세포에 특이적으로 결합하는 간수용체 영상용 방사성의약품으로 새로이 합성되었다. 간섬유화를 유발하는 dimethylnitrosamine (DMN)을 투여한 간 손상 휜쥐 모델에서 ^(99m)Tc-LSa의 역동학적인 간섭취를 조사하고 간효소치의 변화와 조직학적 소견을 비교하여, LSA의 간섭취가 간기능의 변화를 반영하는지를 연구하였다. 대상 및 방법: SD계 흰쥐에 DMN를 27 mg/kg으로 복강 내 주사하여 급성 간손상을 유도하고 대조군과 비교하였다. DMN을 주사한 흰쥐를 3일(DMN-3), 8일(DMN-8), 21일(DMN-21)에 ^(99m)Tc=LSA (1,665 mg/kg) 29 MBq를 정맥 주사하여, 30분 동안 동적 영상을 획득하고 간과 신장부위에 관심영역을 설정하여 간과 심장부위의 시간방사능 곡선을 얻었다. 간기능 평가를 위해 시간방사능 곡선을 이용하여 간섭취지수와 혈중제거지수를 구하였고 곡선 최적화를 시행하였다. DMN 투여군과 대조군의 간효소치의 변화와 간조직의 광학현미경 소견을 비교하였다. 결과: 대조군에서는 ^(99m)Tc-LSA가 빠르게 간에 섭취되고 혈중에서 제거되었으나 DMN을 처리한 군에서는 간섭취가 낮았다. 간섭취지수의 비교에서 대조군에 비해 DMN 처리군에서 유의하게 간섭취지수가 낮았다(DMN-3: 0.842, DMN-8: 0.898, DMN-21: 0.91, 대조군: 0.96, p<0.05). 혈중제거지수의 비교에서도 대조군에 비해 DMN 처리군에서 혈중제거지수가 유의하게 높았다(DMN-3: 0.731, DMN-8: 0.654, DMN-21: 0.604, 대조군: 0.473, p<0.05). 비선형 회귀분석에서 R_(2) 값은 0.9이상으로 좋은 일치를 보였고, 대조군에ㅓ K값이 DMN처리군에 비해 크고(DMN-3: 0.28, DMN-8: 0.41, DMN-21: 0.46, 대조군: 0.97, p<0.05), T_(1/2)값은 작았다(DMN-3: 2.5, DMN-8: 1.7, DMN-21: 1.5, 대조군: 0.7, p<0.05). 간효소치의 변화는 DMN-3군에서는 대조군에 비해 상승하였으나 DMN-8, DMN-21군에서는 간효소치의 상승이 관찰되지 않았다. 간조직 소견의 경우 DMN-3군에서 중심정맥 주위에 괴사가 관찰되었으나 DMN-8군, DMN-21군에서는 미약한 정도의 염증세포 침윤만이 관찰되었다. 결론: ^(99m)Tc-LSA 간신티그래피의 간섭취 정도는 간손상과 반비례하였으며 간섭취의 변화는 조직학적 손상이 심한 정도와 간손상후 회복되는 과정을 반영하여 주었다. ^(99m)Tc-LSA 간신티그래피가 간손상을 평가하고 간손상후 회복되는 과정을 추적하는 간수용체 영상용 방사성 의약품으로 사용될 수 있을 것으로 생각된다. Objects: ^(99m)Tc-lactosylated human serum albumin(LSA) is a newly synthesized radiopharmaceutical that binds to asialoglycoprotein receptors, which are specifically presented on the hepatocyte membrane. Hepatic uptake and blood clearance of LSA were evaluated in rat with acute hepatic injury induced by dimethylnitrosamine(DMN) and results were compared with corresponding findings of liver enzyme profile and these of histologic changes. Materials and Methods: DMN (27 mg/kg) was injected intraperitoneally in Sprague-Dawley rat to induce acute hepatic injury. At 3(DMN-3), 8(DMN-8), and 21(DMN-21) days after injection of DMN, LSA injected intravenously, and dynamic images of the liver and heart were recorded for 30 minutes. Time-activity curves of the heart and liver were generated from regions of interest drawn over liver and heart area. Degree of hepatic uptake and blood clearance of LSA were evaluated with visual interpretation and semiquantitative analysis using parameters (receptor index : LHL3 and index of blood clearance : HH3), analysis of time-activity curve was also performed with curve fitting using Prism program. Results: Visual assessment of LSA images revealed decreased hepatic uptake in DMN treated rat, compared to control group. In semiquantitative analysis, LHL3 was significantly lower in DMN treated rat group than control rat group (DMN-3:0.842, DMN-8: 0.898, DMN-21: 0.91, Control: 0.96, p<0.05), whereas HH3 was significantly higher than control rat group (DMN-3: 0.731, DMN-8: 0.654, DMN-21: 0.604, Control: 0.473, p<0.05). AST and ALT were significantly higher in DMN-3 group than those of control group. Centrilobular necrosis and infiltration of inflammatory cells were most prominent in DMN-3 group, and were decreased over time. Conclusion: The degree of hepatic uptake of LSA was inversely correlated with liver transaminase and degree of histologic liver injury in rat with acute hepatic injury.

Intracavitary Radiation Therapy for Recurrent Cystic Brain Tumors with Holmium-166-Chico : A Pilot Study

Ha, Eun Jin,Gwak, Ho-Shin,Rhee, Chang Hun,Youn, Sang Min,Choi, Chang-Woon,Cheon, Gi Jeong The Korean Neurosurgical Society 2013 Journal of Korean neurosurgical society Vol.54 No.3

Objective : Intracavitary injection of beta-emitting radiation source for control of cystic tumors has been tried with a benefit of localized internal radiation. The authors treated cystic brain tumor patients with Holmium-166-chitosan complex (Ho-166-chico), composed of a beta-emitting radionuclide Holmium-166 and biodegradable chit polymer, and evaluated the safety and effective measurement for response. Methods : Twenty-two patients with recurrent cystic brain tumor and/or located in a deep or eloquent area were enrolled in this pilot study. The cyst volume and wall thickness were determined on CT or MRI to assess radiological response. The activity of Ho-166-chico injected via Ommaya reservoir was prescribed to be 10-25 Gy to the cyst wall in a depth of 4 mm. Results : There was neither complications related to systemic absorption nor leakage of Ho-166-chico in all 22 patients. But, two cases of oculomotor paresis were observed in patients with recurrent craniopharyngioma. Radiological response was seen in 14 of 20 available follow-up images (70%). Seven patients of 'evident' radiological response experienced more than 25% decrease of both cyst volume and wall thickness. Another 7 patients with 'suggestive' response showed decrease of cyst volume without definitive change of the wall thickness or vice versa. All patients with benign tumors or low grade gliomas experienced symptomatic improvement. Conclusion : Ho-166-chico intracavitary radiation therapy for cystic tumor is a safe method of palliation without serious complications. The determination of both minimal effective dosage and time interval of repeated injection through phase 1 trial could improve the results in the future.

Nrf2-Heme oxygenase-1 modulates autophagy and inhibits apoptosis triggered by elevated glucose levels in renal tubule cells

Joo Heon Kim,김경민,Jin Uk Jeong,Jong-Ho Shin,신재민,방기태 대한신장학회 2019 Kidney Research and Clinical Practice Vol.38 No.3

Background: Autophagy is a highly balanced process in which lysosomes remove aged and damaged organelles and cellular proteins. Autophagy is essential to maintain homeostasis in the kidneys. Methods: Using human renal tubule cells HK-2, we assessed the impact of high glucose (HG) on autophagy. We also evaluated the capability of sulforaphane (SFN) to protect the HK-2 cells from HG-induced apoptosis by modulating autophagy. Results: SFN modulated autophagy and decreased apoptosis in the HK-2 cells that were cultured in 250 mM glucose medium for two days. The reactive oxygen species (ROS) levels increased, as expected, in the cells cultured in the 250 mM glucose medium. However, the SFN decreased the ROS levels in the HK-2 cells. The overexpression of heme oxygenase-1 (HO-1) by SFN decreased the expression of LC3 and beclin-1. LC3 and beclin-1 were involved in the downregulation of caspase-3 that was observed in the HG-induced cells. Conclusion: The activation of nuclear factor E2-related factor 2 (Nrf2)-HO-1 inhibited ROS expression and subsequently attenuated autophagy and cell apoptosis after HG injury was decreased. HG injury led to the activation of autophagy and HO-1 in order to combat oxidative stress and protect against cell apoptosis. Therefore, HO-1 activation can prevent ROS development and oxidative stress during HG injury, which considerably decreases autophagy and apoptosis.

Antioxidant and Anti-Inflammatory Effects of Rhei Rhizoma and Coptidis Rhizoma Mixture on Reflux Esophagitis in Rats

Kwon, O Jun,Kim, Min Yeong,Shin, Sung Ho,Lee, Ah Reum,Lee, Joo Young,Seo, Bu-il,Shin, Mi-Rae,Choi, Hyun Gyu,Kim, Jeong Ah,Min, Byung Sun,Kim, Gyo-Nam,Noh, Jeong Sook,Rhee, Man Hee,Roh, Seong-Soo Hindawi Publishing Corporation 2016 Evidence-based Complementary and Alternative Medic Vol.2016 No.-

<P>The purpose of this study was to investigate the antioxidant and anti-inflammatory effects of the combined extract of Rhei rhizoma and Coptidis rhizoma (RC-mix) in experimental model of acute reflux esophagitis. The antioxidant activity was assessed by<I> in vitro</I> 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays. RC-mix was given at 100, 200, and 400 mg/kg body weight 2 h prior to induction of reflux esophagitis (RE). After 5 h, the effects of RC-mix treated rats were compared with those of normal and control rats. The representative flavonoid contents of RC-mix, such as sennoside A, epiberberine, coptisine, palmatine, and berberine, were detected using HPLC. The elevated esophageal mucosa damage was markedly ameliorated by RC-mix treatment in a dose-dependent manner. Furthermore, the administration of RC-mix reduced the increase of serum reactive oxygen species (ROS) and peroxynitrite (ONOO<SUP>−</SUP>). The improvement of superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) levels were marked in the group given RC-mix. Moreover, the elevation of inflammatory mediators and cytokines by nuclear factor-kappa B (NF-<I>κ</I>B) activation in control rats decreased by RC-mix pretreatment. These results indicate that RC-mix treatment reduces the pathological states of esophagitis<I> via</I> regulating NF-<I>κ</I>B mediated inflammation related to oxidative stress. </P>

유한요소 모델링에 의한 절대코일 와전류신호 해석

신영길,이정호 국립7개대학공동논문집간행위원회 2003 공업기술연구 Vol.3 No.-

Eddy current testing(ECT) is used in a variety of industries to find discontinuity and make property measurements, particularly, in the maintenance inspection of aircraft and steam generator tubes. There are two basic types of probe; one is absolute and the other is differential. Since there are many factors influencing the ECT signal, differential type probes are frequently used. However, differential signals are processed to eliminate common factors of the two coil impedance so that signal interpretation is not straightforward. On the other hand, the response of the absolute coil is rather straightforward in view of the electromagnetic theory. In this paper, normalized impedance plane diagrams are prepared and analysed by the finite element modeling for the efficient interpretation of absolute signals. The effects of lift-off, fill-factor, conductivity, operating frequency, and thickness variation of the test specimen are presented with signals from planar and tubular geometry. Knowledge of loci due to various factors on the impedance plane will allow us to separate factors, thereby eliminating errors and increasing test reliability.

Euonymus alatus 추출뭉의 실험적 간 손상 억제

신숙정,이병용,신동근,이정호 Official Journal of the Korean society for immunol 2001 Immune Network Vol.1 No.3

다축 제어 시뮬레이터 링크부의 동특성에 관한 연구

정상화,류신호,박용래 朝鮮大學校 機械技術硏究所 2001 機械技術硏究 Vol.4 No.1

차량개발과정에 있어서 완성차량에 대한 실험방법은 크게 실차 주행실험과 실험실 재현실험의 두가지로 분류할 수 있다. 이 중 실험실 재현실험은 주어진 실험실내의 공간에서 차량의 주행상태를 반복, 재현함으로써 시간의 절감과 함께 공간 및 환경의 제약에서 벗어날 수 있으며, 실험의 지속적 재현성과 실험중인 차량을 수시로 관찰, 분석할 수 있어 취약부분 및 성능의 조기 확인이 가능한 장점이 있다. 이런 이유로 많은 국외 자동차사에서는 다축 제어 시뮬레이터를 이용한 실험실 재현실험을 활성화하여 차량개발기간의 단축은 물론 높은 신뢰성을 가진 고품질 자동차의 개발에 활용하고 있는 실정이나, 아직까지 국내에서는 수입하여 활용측면에서는 아직 초보단계를 벗어나지 못하고 있다. 본 논문에서는 실험실 재현실험의 구동부인 다축 제어 시뮬레이터에 작용하는 4가지 요소중 3가지 요소인 연직·전후·횡 하중등을 복합적으로 재현할 수 있는 링크 구조를 설계하여 동역학 해석 프로그램인 ADAMS를 이용하여 시뮬레이션을 수행하고, 링크부의 안정성 평가 및 최적모델의 사양을 결정하기 위해 FEM 해석을 하였다. Test in the development of vehicle consist of driving test and simulation test. The last one has many advantages. It can reduse time and cost during development, can overcome the spacial and environmental limitation, and can provides repeatabilities of similar experiments and various data. In these reason, the simulation test is widely used in the developed countries for developing new vehicles and analyzing the dynamic characteristics of vehicle developed.

LaCrO_(3) 후막의 가스 감도 특성

신정호,장재영,김정규,박기철 경북대학교 센서기술연구소 1998 센서技術學術大會論文集 Vol.9 No.1

LaCrO_(3) thick film sensors were fabricated on an alumina substrate by screen printing method. The sensitivities for gases were investigated by varying the heat treatment temperatures of the films. The sensitivities of LaCrO_(3) thick film for Gallo and NH_(3) gases were better than for CO and NO gases. The best condition of heat treatment was 450℃ and the optimal operating temperature of LaCrO_(3) thick film for the highest sensitivity was 400℃. Sensitivities of LaCrO_(3) thick films about at 3000ppm for C_(4)H_(10) and NH_(3) gases were 85% and 95%, respectively.

초음파 이송시스템의 진행파 제어에 관한 연구

정상화,신상문,김태호,서호진,박진완 朝鮮大學校 機械技術硏究所 2007 機械技術硏究 Vol.10 No.1

Methods of major transport system used in many industry fields are conveyor belt, magnetic levitation system and indexing system. It is an indispensable device in many fields and especially it is very important in the factory automation. However, the conventional transport system can damage precision optical components by the contact force and destroy the inner structure of semiconductor by the magnetic field. The new transport system for transporting without damage is required and the ultrasonic wave transport system has been proposed to replace the conventional transport system. In this paper. the object transport system using the ultrasonic wave is developed. Traveling waves are generated through the use of the ultrasonic wave generator to two ends of the beam. The modelling equation on steady state response of ultrasonic vibration is expressed through normal mode expansion. Natural frequency of flexural beam is estimated. Transport direction of the object is analyzed according to phase difference and frequency. In addition, it is verified by experiment.