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.

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>

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.

직경 1˝ 자성관에서의 원격장와전류 탐상 실험 빛 결함신호 특성

신영길,이창준,이정호,이윤태,장권규,송성철,송성진,정태언 국립7개대학공동논문집간행위원회 2002 공업기술연구 Vol.2 No.-

In this study, a remote field eddy current testing system is built to inspect 1˝ diameter ferromagnetic tubes and resulting experimental signals are investigated. To decide the operating frequency, the emf of sensor coil is monitored while the sensor coil is moved away from the exciter. At proper frequency, sudden change would occur in the signal pattern. This also indicates the location of remote field region, so that the distance between coils can be decided. The defect signal contains two defect indications, each appears as the sensor and exciter coil passes a defect. Experimental results show that defect depth can be estimated by comparing the two indications. Also, linear relationship between defect depth and phase signal strength is observed.

韓國産 薔薇科 植物에 관한 本草學的 硏究 I

정종길,황상욱,송호준,신민교 한국전통의학연구소 2004 한국전통의학지 Vol.14 No.1

For the purpose of developing Korean Herbalogy with the plants of Rosaceae which grow wild and is planted in Korea, the these and writings on herbalogy, from literature of successive generations, have been thoroughly investigated and the results obtained as follows: 1. There were totaled to 36 genera and 262 in Korea and among them medicinal plants are 27 genera, 117species, some 44% in total, but the number of species may be added because of the similiar plants. 2. According to sum of 262 species in Rosaceae family, they were classified into Agrimonia genera 3, Potentilla genera 26, Prunus genera 48,pyrus genera 17, Rosa genera 24, Rubus genera 28, Sorbaria genera 17, Spiraea genera 20. Thus it was noticed that Prunus genera was the main kind in total. 3. According to the oriental names which can be used for medical purpose, the medicinal plants belonging to the Rosaceae family were classified as Herba 24, Radix 43, Foilum 31, Fructus 48, Semen 11, cortex 14, Lignum, Ramulus;12 each Flos 3, pericarpium 3, resina 2, the others 6. so Fructus is 24% of all and it is the most applied in the clinical treatments. 4. According to nature and flavour of medicinal plants, they were classified into balance 84, warmth, heat; 44 each, cold, cool; 35 each bitter taste 79, sweet taste 74, sour taste 61 thus it was noticed that balance and bitter taste is the main in nature and flavour of medicinal plants 5. According to meridian tropism of herbs they were classified into liver meridian 50 lung meridian 28, stomach meridian 22, spleen meridian 20, heart meridian 19 thus it was noticed that liver meridian is the main kind 6. According to the Properties and Principal curative action, they were classified into drugs for treating detoxicant 72, drugs for treating febrifugal 55, drugs for invigorating blood circulation 53, drugs for removing dampness 46, drugs for expelling wind and drugs to stop bleeding 38 each, drugs to cure tramatic swelling and drugs for relieving pain 36 each. Thus it was noticed that drugs for treating detoxicant and febrifugal was the main kind 7. It was researched that toxic drugs include minor toxin were 10 kinds From this result, it was revealed that Fructus was the main kind in the plants for medical purpose of Rosaceae. and toxic plants was slightly poisonous that it will be used for clinical treatments more easily. It is considered that many experiments and clinical approaches must be continued to use Rosaceae plants widely.

동종 골수이식 후 만성 이식편대숙주질환과 동반되어 신증후군으로 발현된 IgA 신병증 1예

정철권,김현수,박준성,정성현,조도연,최진혁,남동기,임호영,김명성,신규태,임현이,김효철 대한조혈모세포이식학회 1999 대한조혈모세포이식학회지 Vol.4 No.2

동종 골수이식 후 발생하는 신기능부전은 원인이 다양하여 감별에 어려움이 있다. 만성 GVHD는 흉선의 기능저하에 따른 면역관용의 실패로 발생되는 자가면역현상에 의해 발생되는 것으로 알려져 있으며 드물게 신장을 침범하여 신증후군을 일으키기도 한다. CaA의 용량을 줄이거나 투약중지 후 발생한 만성 GVHD에 동반된 신증후군의 경우 조기에 신조직검사를 시행하여 감별진단하고 CsA의 용량을 증량하거나 재투약하여 좋은 치료 결과를 보일 것으로 기대된다. 저자들은 문헌고찰을 통해 동종 골수이식 후 발생된 신증후군이 유사한 임상양상을 보이며 발생기전에 만성 GVHD와 자가면역현상이 연관되어 있음을 확인하였으며 동종 골수이식 후 신증후군의 임상양상을 보이는 환자에서 병리조직학적으로 lgA 신병증을 진단하고 이러한 lgA 신병증이 발생기전에 만성 GVHD와 자가 면역현상이 연관되어 있을 가능성을 최초로 확인하였으며 CsA를 이용하여 성공적으로 치료한 경험을 하였기에 보고하는 바이다. Renal insufficiency is occasionally encountered in allogeneic bone marrow transplantation and its cause is difficult to ascertain. Chronic graft-versus-host disease (GVHD) related to thymic dysfunction is immune-mediated and involves autoreactivity of T-lymphocytes derived from donor marrow to recipient's major histocompatibility complex(MHC) minor antigens. The clinical mainifestations of chronic GVHD are similar to those of autoimmune disease but kidney involvement is rare. Few cases of nephrotic syndrome with membranous nephropathy or minimal change nephrotic syndrome have been reported to be associated with chronic GVHD in allogeneic bone marrow transplant recipient especially after cyclosporine A(CsA) withdrawal, and these cases have responded well to CsA. Therefore, it is prudent to differentiate the cause of post-transplant renal insufficiency using renal biopsy and to start CsA in a case of nephrotic syndrome associated with chronic GVHD as early as possible. We report a case who had a massive proteinuria during the post-allogeneic marrow transplantation period. The cause of nephrotic syndrome was diagnosed as IgA nephropathy by renal biopsy. The patient was successfully treated with reintroduction of CsA.

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.

韓國産 가지과 植物에 관한 本草學的 硏究

정대기,변종호,신민교,송호준 대한본초학회 1998 大韓本草學會誌 Vol.13 No.1

For the purpose of developing Korean Herbalogy with the plants of Solanceae which grow wild and is planted in Korea, the these and writings on herbalogy, from literature of successive generations, have been throughly investigative and the results obtained were as follows: 1. There were totaled to 13 genera and 26 species in Korea and among them medicinal plants are 11 genera, 19 species, some 73% in total but, the number of species may be added because of the similiar plants. 2. According to the oriental names which can be used for medical purpose, the medicinal plants belonging to the Solanaceae family were classified as Radix 8, Fructus 8, Herba 6 ,Foilum 5, Semen 3, Lignum and Flos 2. 3. According to sum of 26 species in Solanaceae family, they were classified into Solanum genera 8, Physalis and Capsicum genera 3 each, Datura and Nicotiana genera 2 each. Thus it was noticed that Solanum genera was the main kind, some 30% in total. 4. According to the number of species of the origin plants about each chinese materia medicals, they were calssified into HERBA SOLANI LYRATI 3, FRUCTUS CAPSICI and FLOS DATURAE 2 each. 5. According to nature and flavour of medicinal plants, they were classified into cold, cool; 17 each,warmth,heat; 8 each, balance 5 and unidentified 6. Thus it was noticed that cold and cool is the main in nature and flavour of medicinal plants. 6. According to the Properties and Principal curative action, they were classified into Drugs for treating febrifugal and detoxicant 14, Drugs for relieving pain 7, Antitussives . Diuretics . Drugs for invigorating blood circulation. Tonics 4 each, Anthelmintics 3. 7. Comparing to whole medicinal plants 19 kinds, toxic drugs include minor toxin were 3 kinds, 16% of the whole. From this result, It was revealed that the plants for medical purpose in Solanaceae was 73% of the whole, in which RADIX and FRUCTUS were abundunt. It is considered that many experiments and clinical approaches must be continued to use Solanaceae plants widely.