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.

정신분열병에 대한 리스페리돈의 효과 및 안정성

이민수,김용구,김영훈,연병길,오병훈,윤도준,윤진상,이철,정희연,강병조,김광수,김동언,김명정,김상훈,김희철,나철,노승호,민경준,박기창,박두병,백기청,백인호,손봉기,손진욱,양병환,양창국,우행원,이정호,이종범,이홍식,임기영,전태연,정영조,정영철,정인과,정인원,지익성,채정호,한상익,한선호,한진희,서광윤 大韓神經精神醫學會 1998 신경정신의학 Vol.37 No.1

연구목적 : 본 시험의 목적은 임상시험 시작전에 연구자들을 대상으로 PANSS Workshop을 통하여 PANSS, ESRS에 대한 국내에서의 표준화 작업을 구축하고 새로운 정신병 치료제인 리스페리돈의 효과와 안정성을 재확인하여 리스페리돈 사용에 대한 적정화를 이루는데 있다. 연구방법 : 1996년 4월부터 1996년 9월까지 국내 39개 대학병원 정신과에 입원중인 혹은 증상이 악화되어 입원하는 정신분열병 환자 377명을 대상으로 다시설 개방 연구를 시행하였다. 1주일간의 약물 배설기간을 가진후, 리스페리돈을 8주간 투여하였고, 기준점, 1주, 2주, 4주, 그리고 8주후에 평가되었다. 용량은 제1일에는 리스페리돈 1mg씩 1일 2회, 제2일에는 2mg씩 1일 2회, 제3∼7일에는 3mg씩 1일 2회 투여하였다. 이후 환자의 임상상태에 따라 임의로 증량할 수 있으며, 최대 일일 16mg을 초과하지 않도록 하였다. 추체외로 증상을 조절하기 위한 투약을 허용하였다. 임상증상 및 부작용의 평가는 PANSS(Positive and Negative Syndrome Scale), CGI(Clinical Global Impression) 그리고 ESRS(Extrapyramidal Symptom Rating Scale)을 사용하였다. 연구결과 : 377명중 343명(91%)이 8주간의 연구를 완결하였다. 치료 종결시점인 8주후 PANSS 총점수가 20% 이상 호전된 경우를 약물 반응군으로 정의할때, 약물반응군은 81.3%였다. 리스페리돈에 반응하는 예측인자로는 발병연령, 이전의 입원 횟수, 유병기간이 관련 있었다. 리스페리돈은 1주후부터 PANSS양성, 음성, 및 일반정신병리 점수상에 유의한 호전을 보여 효과가 빨랐다. CGI의 경우도 기준점에 비해 1주후부터 유의한 감소를 나타내었다. ESRS의 경우, 파킨슨 평가점수는 기준점과 비교해 투여 1주, 2주, 4주후 유의하게 증가되었다가 8주후 기준점과 차이가 없었다. Dystonia 평가점수는 1주후만 유의한 증가를 보였으며, dyskinesia 평가점수는 유의한 차이가 없었다. 혈압, 맥박수의 생명징후 및 일반 혈액학 검사, 생화학적 검사, 심전도 검사에서 유의한 변화는 없었다. 결 론 : 이상의 다시설 개방 임상 연구를 통해 리스페리돈은 정신분열병 환자에서 양성증상뿐만 아니라 음성증상 및 전반적인 증상에도 효과적인 것으로 사료된다. 보다 명확한 평가를 위해서는 다른 항정신병약물과의 이중맹검 연구가 필요할 것으로 생각되며, 또한 장기적 치료에 대한 평가도 함께 이루어져야 하겠다. Objective : The purpose of this study was to investigate the efficacy and safety of risperidone in the treatment of Korean schizophrenic patients. Method : This multicenter open study included 377 schizophrenic patients drawn from 39 university hospitals. After a wash-out period of 1 week, the schizophrenic patients were treated with risperidone for 8 weeks and evaluated at 5 points ; at baseline, and 1, 2, 4 and 8 weeks of treatment. The dose was increased from 2mg/day(1mg twice daily) to 6mg/day(3mg twice daily) during the first week and adjusted to a maximum of 16mg/day over the next 7 weeks according to the patient's clinical response. Medication to control extrapyramidal symptoms was permitted. The psychiatric and neurological status of the patients was assessed by PANSS, CGI, and ESRS scales. Results : 343(91%) of 377 patients completed the 8-week trial period. Clinical improvement, as defined by a 20% or more reduction in total PANSS score at end point, was shown by 81.3% of patients. The predictors of response to risperidone were associated older age, shorter duration of illness, fewer previous hospitalization. Risperidone had rapid onset of action ; a significant decrease of the total PANSS and three PANSS factor(positive, negative, general), and CGI was already noticed at the end of first week. For the ESRS, parkinsonism rating scores were significantly increased until week 4 comparing with baseline. Dystonia rating scores were significantly increased until week 1, and dyskinesia rating scores were not significantly changed during the study. Laboratory parameters including vital sign, EKG, hematological, and biochemical values showed no significant changes during the trial. Conclusions : This study suggests that risperidone is generally safe and effective against both the positive and negative symptoms in our group of patients.

Induction of heme oxygenase-1 protects against podocyte apoptosis under diabetic conditions

Lee, Sang Choel,Han, Seung Hyeok,Li, Jin Ji,Lee, Sun Ha,Jung, Dong-Sub,Kwak, Seung-Jae,Kim, Seung Hye,Kim, Dong Ki,Yoo, Tae-Hyun,Kim, Jin Hyun,Chang, Se-Ho,Han, Dae Suk,Kang, Shin-Wook International Society of Nephrology 2009 Kidney international Vol.76 No.8

Heme oxygenase-1 (HO-1) is an anti-oxidant enzyme normally upregulated in response to oxidant injury. Here we determined the role of HO-1 in podocyte apoptosis in glomeruli of streptozotocin-treated rats and in immortalized mouse podocytes cultured in media containing normal or high glucose. HO-1 expression, its activity, the ratio of Bax/Bcl-2 protein, and active caspase-3 fragments were all significantly higher in isolated glomeruli of diabetic rats and in high glucose–treated podocytes. These increases were inhibited by zinc protoporphyrin treatment of the rats or by HO-1 siRNA treatment of the podocytes in culture. The number of apoptotic cells was also significantly increased in the glomeruli of diabetic rats and in high glucose–treated podocytes. Inhibition of HO-1 accentuated the increase in apoptotic cells both in vivo and in vitro. Our findings suggest that HO-1 expression protects against podocyte apoptosis under diabetic conditions.

N-acetyl cysteine inhibits H2O2-mediated reduction in the mineralization of MC3T3-E1 cells by down-regulating Nrf2/HO-1 pathway

( Daewoo Lee ),( Sung Ho Kook ),( Hyeok Ji ),( Seung Ah Lee ),( Ki Choon Choi ),( Kyung Yeol Lee ),( Jeong Chae Lee ) 생화학분자생물학회(구 한국생화학분자생물학회) 2015 BMB Reports Vol.48 No.11

There are controversial findings regarding the roles of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway on bone metabolism under oxidative stress. We investigated how Nrf2/HO-1 pathway affects osteoblast differentiation of MC3T3-E1 cells in response to hydrogen peroxide (H2O2), N-acetyl cysteine (NAC), or both. Exposing the cells to H2O2 decreased the alkaline phosphatase activity, calcium accumulation, and expression of osteoblast markers, such as osteocalcin and runt-related transcription factor-2. In contrast, H2O2 treatment increased the expression of Nrf2 and HO-1 in the cells. Treatment with hemin, a chemical HO-1 inducer, mimicked the inhibitory effect of H2O2 on osteoblast differentiation by increasing the HO-1 expression and decreasing the osteogenic marker genes. Pretreatment with NAC restored all changes induced by H2O2 to near normal levels in the cells. Collectively, our findings suggest that H2O2-mediated activation of Nrf2/HO-1 pathway negatively regulates the osteoblast differentiation, which is inhibited by NAC. [BMB Reports 2015; 48(11): 636-641]

FK506이 T 림프구 사멸에서 활성산소 생성에 미치는 영향

이호균(Ho Kyun Lee),정상영(Sang Young Chung),최수진나(Soo Jin Na Choi) 대한외과학회 2009 Annals of Surgical Treatment and Research(ASRT) Vol.77 No.5

Purpose: Tacrolimus (FK506) has been widely used as an immunosuppressant in organ transplanted recipients to suppress organ rejection phenomenon. We investigated the role of oxidative stress and heme oxygense-1 by FK506 on human Jurkat T cells. Methods: The cells viability was examined by DAPI stain, enzyme activity of caspase family proteins, and western blotting for Baks, PUMA, iNOS, HO-1. Cells were cultured in the absence or presence of CoPPIX or ZnPPIX and the fluorescence intensity was analyzed using a flow cytometry. Results: Treatment with FK506 increased the generation of reactive oxygen species (ROS), including hydrogen peroxide and superoxide anion, and NO in Jurkat cells in a dose-dependent manner. Immunohistochemistry and Western blot analysis data revealed the hemoxygenase-1 (HO-1) was induced by the addition of FK506 in Jurkat cells. Induction of CoPP, HO-1 inducer, resulted in decreased intracellular H₂O₂ and NO concentrations. Instead ZnPP, an HO-1 competitive inhibitor did it reversely. In addition, ZnPP regulates iNOS protein synthesis by inhibition of HO-1. Conclusion: Increase of HO-1 expression would induce to decrease the intracellular H₂O₂ and NO concentrations. Also, HO-1 would regulate iNOS protein synthesis. Consequently, we can expect the regulation of HO-1 expression with concomitants use of FK506 to suppress organ rejection phenomenon by enhancing apoptosis.

류건휴의 『溪湖學的』과 『異學集辨』에 나타난 후기 영남학파의 ‘도통’과 ‘벽이단’ 의식

이상호(Lee Sang-ho) 한국동양철학회 2009 동양철학 Vol.0 No.32

이 논문은 19세기 초 호파계열에서 병호시비를 주도했던 류건휴의 『계호학적』과 『이학집변』을 중심으로, 후기 영남학인들의 도통과 이단에 대한 인식을 살펴보고 있다. 특히 이 두 책은 이황의 적통이 누구에게 이어졌는지를 중심으로 진행된 병호시비의 중요한 이론적 근거가 되었던 것으로, 향후 정재학파의 이론적 토대에 중요한 영향을 끼쳤다. 『계호학적』은 이황의 도통이 이상정에게 있다는 사실을 밝히기 위해 이상정의 어록과 문집 내용을 발췌하여 이황의 입장과 비교할 수 있도록 편집한 책이다. 『근사록』과 같은 편집체계를 통해 이상정의 철학이 이황과 완전하게 일치한다는 사실을 드러내려고 했던 것이다. 이에 비해 『이학집변』은 퇴계학의 정통성을 공고히 하기 위한 작업으로서의 성격을 가지고 있다. 이단에 대한 강한 비판을 통해 주자학 내에서의 퇴계학 정통성을 공고히 하려고 했던 것이다. 이와 같은 류건휴의 작업은 당시의 시대적 상황 속에서 ‘도통 확립의 필요성’과 이단 비판을 통한 ‘정학正學 보존의 노력’에 따른 것으로, 이를 통해 우리는 후기 영남학파의 인물들이 무엇을 중심으로 생각하면서 살아갔는지를 잘 알 수 있다. 정치적으로 이미 중앙으로부터 소외된 상태에서 그들 스스로의 자긍심과 자부심을 만들어 내고 있으면, 동시에 스스로 주자학적 정통에서 있음을 밝힘으로써 학문적인 우위성을 확보하려는 노력의 일환인 것이다. 더불어 기호학파로부터 받을 수 있는 조금의 의심에 대해서도 철저하게 불식시켜 나감으로써, 자신들 학문의 정통성을 드러내려고 했던 것이다. The purpose of this essay is to examine cognizance of 'taotung(道統: Legitimate Transmission of the Orthodoxy)' and heresy of late Yeungnam School, focused on Ryu, Geon-Hyu's "Gyeho-hakjeok(溪湖學的)" and "Yihak-jipbyeon(異學集辨)", which took the lead in Byungho Dispute(屛虎是非) in Ho faction of the early 19th century. Specially, for the next, these books affected theoretical foundation of Jeongjae School, become theoretical foundation of ByungHo Dispute which is gone on problem of whom the main line of descent of Lee Hwang is continued. Geyho-hakjeok is the book which we can compare to standpoint of Lee Hwang extracting contents of collection of works and quotations of Lee, Sang-Jeong by the book, to define the fact there is the main line of descent of Lee Hwang in Lee, Sang-Jeong. Through a system of edit like Keunsarok(『近思錄』), we can see that philosophy of Lee, Sang-Jeong perfectly correspond with it of Lee Hwang. In comparison, Yihak-jipbyeon has character as work for solidifying legitimate of Toegye's Philosophy. It is to solidify legitimate of Toegye's Philosophy in Zhuxi Studies through strong criticism about heresy. These works of Ryu, Geon-Hyu is caused by 'effort of preservation of Righteousness Philosophy(正學)' through 'necessity of establishing Taotung' and criticism of heresy, on this wise, we can see about what persons of Yeungnam School thought and lived. They make own self-esteem and pride in politically a shunned situation from the central government, at the same time, this is part of effort to secure scientific superiority, by defining that which is on legitimacy of Zhuxi Studies; besides, they was going to reveal legitimacy of own science, by eliminating a little suspicion from kiho School(畿湖學派).

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.

위장관을 침범한 Henoch-Soho¨nlein purpura 1예

이승곤,김채규,서종옥,이호영,이호준,정회상,박유환,정춘해 조선의대 1996 The Medical Journal of Chosun University Vol.21 No.2

외상에 의한 근관내 석회화 변성 치아의 처치

이성룡,이난영,이창섭,이상호 大韓小兒齒科學會 2004 大韓小兒齒科學會誌 Vol.31 No.2

외상 치아에서 일반적으로 발생할 수 있는 합병증으로는 치수 충혈, 내출혈, 근관내 석회화 변성, 외흡수, 치수괴사, 유착 등이 있다. 치아의 근관내 석회화 변성은 치아가 외상을 받았을 경우, 발생할 수 있는 이러한 합병증의 하나이다. 석회화 변성은 여러 요소에 의해 확인될 수 있는데 임상적으로는 치관의 황색 계통의 변색과 방사선학적으로는 치수강을 포함한 근관의 부분적, 혹은 전체적인 협착을 특징으로 한다. 이러한 석회화 변성이 발생할 경우, 치수 괴사로 이행되기도 하는데, 모두 치수 괴사로 이행되는 것은 아니며 따라서 근관 치료에 앞서 적절한 검사 및 관찰이 필요하다. 본 증례는 만 9세의 여아가 놀던 중 친구의 머리에 부딪혀 상악 중절치의 외상(subluxation)을 받고 내원한 경우로 지속적인 임상적, 방사선학적 검사를 시행한 결과 근관내 석회화 변성이 관찰되었다. 검사 초기에는 임상적으로 경미한 치관의 변색만 보였을 뿐, 전기 치수 검사(EPT)에서는 특이한 소견은 보이지 않았다. 그 후 전기 치수 검사를 이용한 지속적인 검사 결과, 그 반응의 정도가 점차 감소되었으나, 근관 치료는 좀 더 유보하고 관찰하기로 하였다. 외상 후 20개월 정도 지나서는 전기 치수 검사를 이용한 검사에 거의 반응을 보이지 않았고, 근관의 완전 협착과 치관의 황색 계통의 변색이 관찰 되었다. 이에 치수 괴사로 이행되는 것을 막고 치관의 변색술을 시행하기 위하여 근관 치료를 시행하고 그 결과를 보고하는 바이다. Pulp canal obliteration(PCO) is seen commonly in dental pulp after traumatic tooth injuries and is recognized clinically as early as 3 monthly after injury. Pulp canal obliteration is characterized by deposition of hard tissue within the root canal space and yellow discoloration of the clinical crown. Opinion differs among practitioners as to whether to treat these cases upon early detection of PCO or to observe them until symptoms or radiographic signs of pulpal necrosis are detected. PCO may make root canal treatment necessary because of the development of apical periodotitis, is or for cosmetic reasons. If carefully executed, root canal treatment in teeth with an PCO is hightly successful and may act as a basis for internal bleaching. During a game. a 12-year-old girl was hit in the face. At that time, she was diagnosis a subluxation of the maxillary right central incisor. At the 24-month recall examination, a root canal of the tooth had been calcified and discolored gradually. We performed endodontic treatment to prevent perfect pulp canal obliteration and internal bleaching.

치아 교환기 어린이에서 근단변위부분층 판막술을 이용한 하악 거대 협소대의 위치

이성룡,오유향,이난영,이창섭,이상호 大韓小兒齒科學會 2004 大韓小兒齒科學會誌 Vol.31 No.4

영구치의 맹출 지연이 발생하는 원인은 다양하다. 유치의 만기 잔존과 조기 상실, 과잉치나 치아종과 같은 이형물의 존재등과 같이 비정상적인 경조직 인자에 의해 발생할 수 있고, 치은 판개 조직(opercula)과 같은 상부 치은 조직의 섬유성 비후나 소대의 과증식과 같은 연조직성 인자에 의해 발생하기도 한다. 영구치의 맹출 지연시의 공간의 상실 및 영구치의 비정상적인 맹출, 그리고 그에 따른 치열궁의 비대칭과 같은 교정적 문제와 대합치의 정출 등에 의한 교합적인 문제등이 발생할 수 있어 조기에 진단하여 처치하는 것이 중요하다. 본 증례에서는 12세 남자 아이가 충치가 많고 치아가 나오지 않는다는 것을 주소로 내원하여 진단한 결과, 하악 좌측 소구치들이 맹출하지 못하고 매복되어 있는 것을 알 수 있었다. 원인은 맹출 공간이 부족하였고 동시에 거대 협소대가 치아의 맹출을 방해하는 것으로 파악되었다. 이에 대한 처치로 우선 공간을 획득하고 난 후, 부착치은의 회복과 맹출 촉진을 위해 근단변위부분층 판막술을 시행하였다. The mandibular buccal frenum becomes a problem when its attachment is too close to the marginal gingival. Heavy buccal frenum mucogingivally results in insufficient attached gingiva, inadequate vestibular depth and also difficulty in eruption of mandibular premolar. The aim of this study is to demonstrate the effectiveness of apically positioned partial-thickness flap as adequate mothod in order to remove heavy buccal frenum and expose impacted teeth. The author presents the case of a 12-year-old boy. He had problems that was prolonged eruption of #34, #35 due to high pull buccal frenum. After space regaining for normal eruption of #34, #35, we performed apically positioned partial-thickness flap on #34,35 area. As a results, we confirmed that eruption of #34, #35 has been processed normally. And vestibular depth, position of buccal frenum and width of attached gingival was within a normal range. Decrease in muscle pull, adequate width of attached gingiva and increased vestibular depth can be expected from this treatment.