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>

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.

특발성 경련질환으로 오인된 원발성 부갑상선기능저하증 1례

신성하,최정영,김준기,고영춘,조상욱,김순호,임중규 全南大醫大 2001 전남의대학술지 Vol.37 No.1

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

가오싱지엔 문학의 의의 : With the Focus on His Novels 장편소설을 위주로

신정호 全南大學校 人文科學硏究所 2002 용봉인문논총 Vol.31 No.-

콩나물의 asparagine 함량에 미치는 요인 구명

정연신,손태호,Krishna Hari Dhakal,이정동,황영현 경북대학교 농업과학기술연구소 2008 慶北大農學誌 Vol.26 No.-

알코올의 숙취해독에 뛰어난 효과가 있는 것으로 알려진 sparagine은 콩나물의 뿌리에 함량이 가장 많은 것으로 알려져 있다. 본 연구논문에서는 콩나물 뿌리 발생에 미치는 재배실의 온도, 일당 관수횟수, 재배일수 및 동일용기에 사용한 콩 량에 대한 영향을 조사하여 얻어진 연구결과를 요약하면 다음과 같다. 1. 아가통과 풍산나물콩의 수율은 재배일수에 따라 경시적으로 증가하였으며, 재배실 온도가 20℃에서 보다 30℃에서 높았으며, 콩나물의 수율은 5회 관수, 8일 재배시 가장 높았다. 2. 아가콩과 풍산나물콩의 콩나물 부위별 건물중의 비율은 자엽이 가장 많았고 뿌리가 가장 낮았으며, 재배실 온도가 20℃에서 보다 30℃에서 비율이 더 높았다. 3. 아가콩의 sparagine 함량은 재배실 온도 30℃에서 5회 관수 8일 재배한 하배축에서 18.9%로 가장 높게 나타났다. 4. 풍산나물콩의 sparagine 함량은 재배일수가 길수록, 재배온도가 높은 경우 높았으며, 하배축에서 가장 높았고, 30℃에서 2회 관수 8일 재배시 하배축에서 18.8%로 가장 높게 나타났다. 5. 아가콩은 300g, 풍산나물콩은 500g 치상시 수율이 가장 높았으며, 잔뿌리의 수는 아가콩과 풍산나물콩 모두 치상량이 증가함에 따라 증가하는 경향이었다. It is known that the content of asparagine, an excellent detoxifying substance of alcohols in human body, is the highest in the roots of soy-sprout. At the same time, it is inferred that soy-sprouts producing more roots are better for detoxifying. In this experiment, the effects of room temperatures on number of watering per day, and duration of soy-sprout culture were carefully investigated. Some of the results obtained are as follows; 1. The yield rate of soy-sprouts for Agakong and Pungsannamulkong was continuously increased up to 9 days. It was higher in room temperature of 30℃ than in 20℃ and was the highest at 8th day of culture with 5 times of watering per day. 2. The asparagine content in soy-sprouts of Agakong and Pungsannamulkong was the highest in cotyledon and the lowest in roots. This rate was higher in the room temperature of 20℃ than in 30℃. 3. The highest asparagine content of soy-sprout of Agakong was 18.9%, obtained in the room temperature of 30℃, cultivated for 8 days with 5 times of watering per day. 4. The highest asparagine content of Pungsannamulkong was 18.8%, obtained in hypocotyl cultivated in the room temperature of 30℃ for 8 days with the number of 2 times watering per day. 5. When an cultivation apparatus of 5 liters volume was used, the optimum seed amount for the highest yield rate was 300g for Agakong and 500g for Pungsannamulkong. At the same time, the number of lateral roots showed increasing tendency with more amounts of soybean seeds used.