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.

Heme oxygenase-1 induced by desoxo-narchinol-A attenuated the severity of acute pancreatitis via blockade of neutrophil infiltration

Bae, Gi-Sang,Kim, Dong-Goo,Jo, Il-Joo,Choi, Sun-Bok,Kim, Myoung-Jin,Shin, Joon Yeon,Kim, Dong-Uk,Song, Ho-Joon,Joo, Myungsoo,Park, Sung-Joo ELSEVIER 2019 INTERNATIONAL IMMUNOPHARMACOLOGY Vol.69 No.-

<P><B>Abstract</B></P> <P>Heme oxygenase-1 (HO-1) has an anti-inflammatory action in acute pancreatitis (AP). However, its mechanism of action and natural compounds/drugs to induce HO-1 in pancreas are not well understood. In this study, we investigated the regulatory mechanisms of HO-1 during AP using desoxo-narchinol-A (DN), the natural compound inducing HO-1 in the pancreas. Female C57/BL6 Mice were intraperitoneally injected with supramaximal concentrations of cerulein (50 μg/kg) hourly for 6 h to induce AP. DMSO or DN was administered intraperitoneally, then mice were sacrificed 6 h after the final cerulein injection. Administration of DN increased pancreatic HO-1 expression through activation of activating protein-1, mediated by mitogen-activated protein kinases. Furthermore, DN treatment reduced the pancreatic weight-to-body weight ratio as well as production of digestive enzymes and pro-inflammatory cytokines. Inhibition of HO-1 by tin protoporphyrin IX abolished the protective effects of DN on pancreatic damage. Additionally, DN treatment inhibited neutrophil infiltration into the pancreas via regulation of chemokine (C-X-C motif) ligand 2 (CXCL2) by HO-1. Our results suggest that DN is an effective inducer of HO-1 in the pancreas, and that HO-1 regulates neutrophil infiltration in AP via CXCL2 inhibition.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Desoxo-narchinol-A (DN) is a natural compound of HO-1 inducer in pancreas. </LI> <LI> Mechanism of DN-induced HO-1 is mediated by MAPK/Activator Protein-1/HO-1 signaling. </LI> <LI> DN-induced HO-1 blocks neutrophil infiltration into pancreas via inhibition of CXCL2. </LI> <LI> DN inhibits cerulein-induced acute pancreatitis (AP) and AP-associated lung injury. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

hnRNPK-regulated PTOV1-AS1 modulates heme oxygenase-1 expression via miR-1207-5p

( Chang Hoon Shin ),( Seongho Ryu ),( Hyeon Ho Kim ) 생화학분자생물학회(구 한국생화학분자생물학회) 2017 BMB Reports Vol.50 No.4

Antisense transcripts were initially identified as transcriptional noise, but have since been reported to play an important role in the quality control of miRNA functions. In this report, we tested the hypothesis that heterogeneous nuclear ribonucleoprotein K (hnRNPK) regulates miRNA function via competitive endogenous RNAs, such as pseudogenes, long non-coding RNAs, and antisense transcripts. Based on analyses of RNA sequencing data, the knockdown of hnRNPK decreased the antisense PTOV1-AS1 transcript which harbors five binding sites for miR-1207-5p. We identified heme oxygenase-1 (HO-1) mRNA as a novel target of miR-1207-5p by western blotting and Ago2 immunoprecipitation. The knockdown of hnRNPK or PTOV1-AS1 suppressed HO-1 expression by increasing the enrichment of HO-1 mRNA in miR-1207-5p-mediated miRISC. Downregulation of HO-1 by a miR-1207-5p mimic or knockdown of hnRNPK and PTOV1- AS1 inhibited the proliferation and clonogenic ability of HeLa cells. Taken together, our results demonstrate that hnRNPKregulated PTOV1-AS1 modulates HO-1 expression via miR- 1207-5p. [BMB Reports 2017; 50(4): 220-225]

임란 被虜人 홍호연은 누구이며 어떻게 피랍되었는가

신윤호(Shin Yun-ho) 순천향대학교 이순신연구소 2010 이순신연구논총 Vol.- No.14

홍호연(洪浩然, 1582~1657)은 雲海라고도 한다. 1593년, 제2차 진주성전투 이후 나베시마 나오시게 군대에 붙잡혀 일본으로 끌려가 佐賀藩主 나베시마의 家臣이 되어 서예가로 활약했던 인물이다. 그는 조선으로 돌아오려고 하였으나 그 소원을 이루지 못하고 생을 마쳤다. 그가 12세의 어린 나이에 일본으로 건너갔기 때문인지 조선에서의 행적이 남아있지 않다. 그의 출신에 대해서는 거의 알려진 바가 없으며 다만 고향이 산음(현재의 경남 산청지역)이라는 것뿐이었다. 따라서 홍호연의 출생지 및 가족관계를 조사하였으며, 이 과정에서 산청군 오부면 중촌리에 南陽洪氏 마을이 있다는 사실을 발견하였다. 임진왜란 시기에 ‘洪雲海’ 라는 이름이 실려 있는 『南陽洪氏族譜』와 그 일가 인물들의 문집 등을 확보하여 일본 측 사료인『洪浩然傳』과 내용을 대조·분석하였다. 그 결과 홍호연의 아버지는 안제이며, 형제는 맏형 성해, 둘째 형 천해, 동생 진해라는 가족관계를 밝혔다. 400여 년이 지난 이 시점에도 홍호연의 출신을 밝힐 수 있었던 것은 그가 조선 에서 쓰던 성명을 일본에서도 그대로 사용했기 때문이며 그 후손들도 현재까지 홍씨 성을 그대로 유지하고 있었기 때문이다. He is Hong Ho-yeon, penname Un-hae. After(or When) second Jin-ju fortress war broke out at 1593, he was caught by Japanese troops. He became a servant of Saga s Nabesima and then gained a reputation as a calligrapher. He wanted to come back Joseon but ended his life in Japan. At the age of 12, he crossed into Japan. And so, We couldn t find his birth but just knew that his hometown is Saneum (Present Sancheong region, Gyeongnam ). For this reason, I searched for Hong Ho-yeon s birthplace and family relations which almost had disappeared. From these, we found that he had lived in Saneum (Sancheong, Gyeongnam). Comparing「Namyang Mr.Hong genealogy」that includes Hong Un-hae (洪雲海) with「A Hong Ho-yeon s biograpy」written in Japanese, I concluded that his father is An-je, first brother is Sung-hae, second brother is Cheon-hae and younger brother is Jin-hae. He used Joseon name of his own in Japan. so we have easily found Hong Ho-yeon s birth over the past 400 years.

소설의 영화화에 따른 서사성 변환 연구 : 「벌레 이야기」와 「밀양」을 중심으로

신익호(Shin Ik ho) 한국언어문학회 2015 한국언어문학 Vol.93 No.-

In Bug Story and Secret Sunshine, the main character Shin-ae's anguish and religious conflict are described in more detail than the incident which causes her child's miserable sacrifice. Seemingly, Shin-ae tries hard to overcome her despair with christian faith, but she strives to cope with her tragedy within the limitations of human ability. She is not sure of salvation through the christian faith. Conversely, she is obsessed with the idea that she can get over difficulties with her efforts and will, that is to say, through self-deification. She loses her lovely son, but does not give up on her life. Rather, she can support herself, having strong will and hope. Eventually, these efforts lead to the fictional religion. Others who have never experienced her religious conflict, have no right to criticize that she has developed a blessing-oriented faith. Shin-ae's failure of salvation is a result of the religious dogma. Also, it expresses that she is locked in struggle with her will and fictional faith due to the limitation of human ability rather than she apologizes people around her with agape. She has never experienced both self denial as a sinner and a sense of gratitude and repentance which are the essence of christian faith. For this reason, she is not a born again christian, but just a bug. This story not only educates the reader that false religious faith is serious, but also shows univeral sympathy that religious salvation can not solve easily the problems of the human condition. The original novel, Bug Story, and the movie, Secret Sunshine, have differences in characters, surrounding environment, method of narration, structure derived from different genres, thematic consciousness and ending plot, even though they have common factors such as the existential situation and theodicean problems. The first part of the movie describes how the main character's child is kidnapped and killed in the process of settlement in a remote town. This event is portrayed as the climax of agony and anxiety. In the latter half of the film, the mother of the child writhes in desperate agony and faces the existential situation with religious conflict. At the end, a postive life is implied with secret and hopeful light. The main character, Shin-ae, plays the part of a long-suffering wife who acts out a series of deviant behaviors such as a suicide attempt, wrath and cursing in protest toward God after the failure of forgiveness. She is the most round character by means of motion picture techniques. Though she had a good relationship with others and received God's word once, she becomes a person who does not communicate well with others. When she does not find solutions and just feels despair, facing agony and protesting God, believers urge her to recognize the Providence of God and God's will. In this respect, the theodiciean interpretation justifying agony explains that hardship and adversity resulting from sin can be resolved through atonement. However, art questions and defies the Providence of God and deals intensively with the existential situation that superficial religion can not save people in agony.

Glucose deprivation으로 유발된 Neuro 2A 세포의 산화적 손상에 대한 七氣湯의 보호효과

성기호(Ki-Ho Seong),이정섭(Jung-Sup Lee),신선호(Sun-Ho Shin) 대한한의학회 2010 대한한의학회지 Vol.31 No.2

석탄(石灘) 이신의(李愼儀)의 『대학(大學)』 독해(讀解)와 그 특징(特徵)

신창호 ( Chang Ho Shin ) 한국철학사연구회 2012 한국 철학논집 Vol.0 No.35

본고는 석탄 이신의의 『대학차록(大學箚錄)』을 통해, 『대학』을 바라보는 그의 독창적 안목을 고찰하는 작업이다. 이신의(李愼儀, 1551-1627)는 조선 중기의 학자이자 정치가로, 본관은 전의(全義)이고 자는 경칙(景則)이며 호는 석탄(石灘), 시호는 문정(文貞)이다. 그의 『대학차록』은 『대학장구』를 읽고 체득한 내용을 수시로 적은 기록으로 석탄이 정치지도자로서 기초를 다지는 학문의 초기 과정에서 저술되었다. 석탄은 『대학장구』의 체제인 장(章)과 구(句)의 의미를 명확하게 구분하여 분석적 학문방법론의 새 지평을 열었다. 『대학장구』「서」에서는 대학의 핵심이 경(敬)에 있음을 강조하였고, 『대학』이 심(心)과 성(性)을 함께 다루고 있다는 사실도 밝혔다. 『대학(장구)대전』의 경문(經文) 독해에서는 삼강령(三綱領)의 핵심을 명(明)과 신(新)과 지(止)에 달려 있다고 보고, 대학의 ``도(道)``, ``명(明)``과 ``덕(德)``의 맥락을 구체적으로 해석하였다. 또한 명명덕(明明德)과 신민(新民)을 비롯한 『대학』의 여러 개념과 의미를 지(知)와 행(行), 체(體)와 용(用)의 관계로 읽어내며, 성리학을 한층 발전시켰다. 『대학장구』전문(傳文) 독해의 경우, 전 10장 전체에 걸쳐 50여구 하나하나를 분석적으로 검토하였다. 주자의 격물(格物) 이론이 담겨 있는 전5장의 경우, 세 부분으로 나누어 해독하면서, 이치의 궁구와 개별 사물에 대한 격물치지(格物致知), 모든 사물에 대한 물격지지(物格知至)로 나누어 ``이치-공부-효험’의 순서로 정돈하였다. 마지막으로 정치사상의 핵심을 보여준 전10장에서는 혈구(혈矩)의 길을 집중적으로 강조하며, 그것이 목민관의 제일 덕목임을 일러주고 있다. This research is to investigate his creative perspective to Deahak through Seoktan Lee Shin-Ui`s Daehakcharok. Lee Shin-Ui is a scholar and politician in the middle of Joseon Dynasty. His ancestral home is Jeonui. The honor name is Gyeongchik and pen name is Seoktan. The posthumous name is MunJeong. His Daehakcharok was written in the process of taking basic foundation as the politic leader. It was a record that he usually wrote down things realized after reading Deahakjanggu. Seoktan clearly classified the meaning of Jang (chapter) and Gu (phrase) as the structure of Deahakjanggu, and created new realm about the method of classified study. In the preface of Deahakjanggu, he emphasized that the core of Deahak is in Gyeong (敬, respect or honor), and clarified that Deahak deals with Sim (心, mind) and Seong (性, human nature). In the interpretation of Daehakdeajeon, he thought that the core of Samgangnyeong (三 綱領, three doctrines or essential principles) depended on Myeong (明, realizing), Shin (新, taking re-newness), and Ji (止, achieving) as the meaning of ``realizing, taking re-newness, and achieving``, and interpreted the context of Tao (道, the way), Myeong (明, realizing), and Deuk (德, virtue) in detail. In addition, he interpreted various concepts and meaning of Deahak with Myeongmyeongdeuk (明明德, realizing human nature) and Sinmin (新民, renewing people) as relationship with Ji(知, realization), Haeng(行, practice), Che(體, main structure), and Yong (用, dealing with), and developed Neo-Confucianism deeply. In case of the main interpretation of Deahakjanggu, he analytically reviewed 50 phrases one by one throughout 10 total chapters. In case of chapter five which includes Zhuzi`s the theory of Gyeokmul (格物, approaching things or persons), he interpreted it in three parts and classified Gyeokmulchiji(格物致知, approaching things or persons and then realizing their nature) about researching deeply of principle and each thing, and Mulgyeokjiji(物格知至, approaching things or persons and then realizing them) about all things. He arranged in order of ``principleresearching-result`` as well. In final, chapter ten showing the core of politic thought emphasized the way of Hyeolgu(혈矩, considering others` situation through his/her own experience) intensively and informed that it is the best virtue for a governor.

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.

Curcumin protects retinal pigment epithelial cells against oxidative stress via induction of heme oxygenase-1 expression and reduction of reactive oxygen

Woo, Je Moon,Shin, Da-Yong,Lee, Sung Ju,Joe, Yeonsoo,Zheng, Min,Yim, Jin Ho,Callaway, Zak,Chung, Hun Taeg Molecular Vision 2012 Molecular vision Vol.18 No.-

<P><B>Purpose</B></P><P>To determine whether curcumin induces expression of the defensive enzyme heme oxygenase-1 (HO-1) and protects cells against oxidative stress in cultured human retinal pigment epithelial cells.</P><P><B>Methods</B></P><P>Effective concentrations and toxicities of curcumin were determined after 3 h of curcumin treatment with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Confluent human retinal pigment epithelium cell lines (ARPE-19) were preincubated with curcumin and oxidatively challenged with H<SUB>2</SUB>O<SUB>2</SUB>. HO-1 expression was determined with western blot analysis. To confirm the protective role of HO-1 in oxidative stress, small interfering RNA (siRNA) against HO-1 or inhibitor of HO-1 was treated with curcumin in retinal pigment epithelium cells. Intracellular levels of reactive oxygen species (ROS) were measured with flow cytometry and confocal microscopy. Apoptosis was evaluated with Annexin V-fluoroscein isothiocyanate staining.</P><P><B>Results</B></P><P>Curcumin had little cytotoxicity at concentrations less than 30 μM, and HO-1 expression was the highest at the 15 μM concentration. At this concentration, curcumin also increased the cytoprotective effect against the oxidative stress of H<SUB>2</SUB>O<SUB>2</SUB> through the reduction of ROS levels in human retinal pigment epithelial cells. Curcumin’s effect on the reduction of ROS was mediated by the increase in HO-1 expression.</P><P><B>Conclusions</B></P><P>Curcumin upregulated the oxidative stress defense enzyme HO-1 and may protect human retinal pigment epithelial cells against oxidative stress by reducing ROS levels.</P>

Upregulation of heme oxygenase-1 by ginsenoside Ro attenuates lipopolysaccharide-induced inflammation in macrophage cells

Kim, Sokho,Oh, Myung-Hoon,Kim, Bum-Seok,Kim, Won-Il,Cho, Ho-Seong,Park, Byoung-Yong,Park, Chul,Shin, Gee-Wook,Kwon, Jungkee The Korean Society of Ginseng 2015 Journal of Ginseng Research Vol.39 No.4

Background: The beneficial effects of ginsenoside species have been well demonstrated in a number of studies. However, the function of ginsenoside Ro (GRo), an oleanane-type saponin, has not been sufficiently investigated. Thus, the aim of the present study was to investigate the anti-inflammatory effects of GRo in vitro using the Raw 264.7 mouse macrophage cell line treated with lipopolysaccharide (LPS), and to clarify the possible mechanism of GRo involving heme oxygenase-1 (HO-1), which itself plays a critical role in self-defense in the presence of inflammatory stress. Methods: Raw 264.7 cells were pretreated with GRo (up to $200{\mu}M$) for 1 h before treatment with 1 mg/mL LPS, and both cell viability and inflammatory markers involving HO-1 were evaluated. Results: GRo significantly increased cell viability in a dose dependent manner following treatment with LPS, and decreased levels of reactive oxygen species and nitric oxide. GRo decreased inflammatory cytokines such as nitric oxide synthase and cyclooxygenase-2 induced by LPS. Moreover, GRo increased the expression of HO-1 in a dose dependent manner. Cotreatment of GRo with tin protoporphyrin IX, a selective inhibitor of HO-1, not only inhibited upregulation of HO-1 induced by GRo, but also reversed the anti-inflammatory effect of GRo in LPS treated Raw 264.7 cells. Conclusion: GRo induces anti-inflammatory effects following treatment with LPS via upregulation of HO-1.