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.

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.

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.

Heme oxygenase-1 (HO-1)/carbon monoxide (CO) axis suppresses RANKL-induced osteoclastic differentiation by inhibiting redox-sensitive NF-κB activation

( Sun-uk Bak ),( Suji Kim ),( Hae-jun Hwang ),( Jung-a Yun ),( Wan-sung Kim ),( Moo-ho Won ),( Ji-yoon Kim ),( Kwon-soo Ha ),( Young-guen Kwon ),( Young-myeong Kim ) 생화학분자생물학회(구 한국생화학분자생물학회) 2017 BMB Reports Vol.50 No.2

Heme oxygenase (HO-1) catalyzes heme to carbon monoxide (CO), biliverdin/bilirubin, and iron and is known to prevent the pathogenesis of several human diseases. We assessed the beneficial effect of heme degradation products on osteoclastogenesis induced by receptor activator of NF-κB ligand (RANKL). Treatment of RAW264.7 cells with CORM-2 (a CO donor) and bilirubin, but not with iron, decreased RANKLinduced osteoclastogenesis, with CORM-2 having a more potent anti-osteogenic effect. CORM-2 also inhibited RANKLinduced osteoclastogenesis and osteoclastic resorption activity in marrow-derived macrophages. Treatment with hemin, a HO-1 inducer, strongly inhibited RANKL-induced osteoclastogenesis in wild-type macrophages, but was ineffective in HO-1^+/-cells. CORM-2 reduced RANKL-induced NFATc1 expression by inhibiting IKK-dependent NF-κB activation and reactive oxygen species production. These results suggest that CO potently inhibits RANKL-induced osteoclastogenesis by inhibiting redox-sensitive NF-κB-mediated NFATc1 expression. Our findings indicate that HO-1/CO can act as an antiresorption agent and reduce bone loss by blocking osteoclast differentiation. [BMB Reports 2017; 50(2): 103-108]

PGA2-induced HO-1 attenuates G2M arrest by modulating GADD45α expression

Yun-Jeong Choe,고경원,Hyein Lee,이선영,Byung-Chul Kim,Ho-Shik Kim,Ho-Shik Kim 대한독성 유전단백체 학회 2015 Molecular & cellular toxicology Vol.11 No.4

Prostaglandin (PG) A2, a cyclopentenone PG, arrested the growth of U2OS cells in the G2M phase. While inducing G2M arrest, PGA2 increased the expression of heme oxygenase-1 (HO-1) at the level of transcription along with the accumulation of ROS and the activation of MAPKs including JNK, p38MAPK, and ERK1/2. Among the MAPKs, the inhibition of p38MAPK by a specific chemical inhibitor SB203580, or by RNA interference, but not JNK or ERK1/2, attenuated the PGA2-induced transcription of HO-1. Nacetylcysteine (NAC), a ROS scavenger, prevented PGA2-induced G2M arrest, p38MAPK activation and transcriptional induction of HO-1. PGA2 also stimulated GADD45α expression at the level of transcription, and the knockdown of GADD45α repressed PGA2- induced G2M arrest. Finally, the knockdown of the HO-1 protein elevated PGA2-induced GADD45α expression as well as G2M arrest. Collectively, these results suggest that PGA2 causes an increase in ROS accumulation which initiates both HO-1 transcription via p38MAPK, and G2M arrest via GADD45α transcription, and HO-1 attenuates G2M arrest by modulating the expression of GADD45α.

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.

『閒汨董』 所載 <韋生傳> 硏究

간호윤 ( Kan Ho-yun ) 한국고전문학교육학회 2007 고전문학과 교육 Vol.14 No.-

This article is focused on ‘the significance of excavated material < Wisaengjeon > which takes 『Hangoldong』 as the subject material, and the misunderstanding about < Wigyungcheonjeon >’. 『Hangoldong』 may have been transcribed in the mid-seventeen century by a transcriber who lived in a period near the disturbances of war. Summaries of inquiry are as followed: ① So far there exist several kinds of < Wisaengjeon >, including ‘kan Ho Yun’ version of < Wisaengjeon >, Korean version of < Wi Dyeon >, ‘Jeo Cho’ version and ‘Yu Jae Young’ version in one category, and < Wigyungcheonjeon > based on 『Godamyoram』 which is along a different path of transcription in the other category. The official title is < Wisaengjeon >. ② The < Wisaengjeon > category is closer to the original copy, while the < Wigyungcheonjeon > was transcribed from a different version copied out of the same bottom book with the < Wisaengjeon >’s. ③ The transcriber of 『Hangoldong』 presumably had experienced the disturbances of war, was morally indignant at invaders, was a person of wide reading, and was an righteous intellectual in a noble family who had an indistinct consciousness of novels. ④ While it can be said that < Wigyungcheonjeon > has lower-quality sentences and less tension compared to < Jusaengjeon >, < Wisaengjeon > may be generously assessed. ⑤ Issues of the representative version and the author of < Wisaengjeon >, which have not been dealt with in this article, may still remain as the future subjects. Particularly, the authors can be studied in the positive point of view, by connecting the Korean version of < Wi Dyeon > with the 『Hangoldong』-based < Wisaengjeon >. Additional articles are expected regarding this matter. In conclusion, clear solutions about authors and in-depth discussions on literary works are encouraged, by informing fellows, seniors and gentlemen that ‘Gan Ho Yun’ version of < Wisaengjeon > has been added to the history of Chinese novels in 17th century.

Carbon monoxide prevents TNF-α-induced eNOS downregulation by inhibiting NF-κB-responsive miR-155-5p biogenesis

Choi, Seunghwan,Kim, Joohwan,Kim, Ji-Hee,Lee, Dong-Keon,Park, Wonjin,Park, Minsik,Kim, Suji,Hwang, Jong Yun,Won, Moo-Ho,Choi, Yoon Kyung,Ryoo, Sungwoo,Ha, Kwon-Soo,Kwon, Young-Guen,Kim, Young-Myeong Nature Publishing Group 2017 Experimental and molecular medicine Vol.49 No.11

<P>Heme oxygenase-1-derived carbon monoxide prevents inflammatory vascular disorders. To date, there is no clear evidence that HO-1/CO prevents endothelial dysfunction associated with the downregulation of endothelial NO synthesis in human endothelial cells stimulated with TNF-α. Here, we found that the CO-releasing compound CORM-2 prevented TNF-α-mediated decreases in eNOS expression and NO/cGMP production, without affecting eNOS promoter activity, by maintaining the functional activity of the <I>eNOS</I> mRNA 3′-untranslated region. By contrast, CORM-2 inhibited MIR155HG expression and miR-155-5p biogenesis in TNF-α-stimulated endothelial cells, resulting in recovery of the 3′-UTR activity of <I>eNOS</I> mRNA, a target of miR-155-5p. The beneficial effect of CORM-2 was blocked by an NF-κB inhibitor, a miR-155-5p mimic, a HO-1 inhibitor and siRNA against HO-1, indicating that CO rescues TNF-α-induced eNOS downregulation through NF-κB-responsive miR-155-5p expression via HO-1 induction; similar protective effects of ectopic HO-1 expression and bilirubin were observed in endothelial cells treated with TNF-α. Moreover, heme degradation products, except iron and <I>N</I>-acetylcysteine prevented H<SUB>2</SUB>O<SUB>2</SUB>-mediated miR-155-5p biogenesis and eNOS downregulation. These data demonstrate that CO prevents TNF-α-mediated eNOS downregulation by inhibiting redox-sensitive miR-155-5p biogenesis through a positive forward circuit between CO and HO-1 induction. This circuit may play an important preventive role in inflammatory endothelial dysfunction associated with human vascular diseases.</P>

에버랜드 전환사채 헐가발행 사건 대법원 판결(2007도4949)의 중대한 오류

Yun,Dong-Ho 한국형사법학회 2010 刑事法硏究 Vol.22 No.1

No 2007Do4949 sentenced by the Supreme Court on 2009. 5. 29 is on so-called the Everland case. The facts of the Everland case can be summarized as follows: The issuance of convertible bonds of the Everland Co. Ltd was made a resolution at a giveaway price in the board of directors by the representative director and managing director. The preemptive right on the convertible bonds was given to shareholders. But the large majority of shareholders gave up subscription. The board decided to issue the convertible bonds not subscribed by the existing shareholders to third party at the same price and conditions. The third party were the son and daughters of the chairman of the Samsung Group. They afterward converted the convertible bonds into the shares of the Everland, and became the largest shareholder of the Everland. In this case the Supreme Court declared that the representative director and managing director should not be punished a criminal breach of trust against the issuing corporation. The core of the Supreme Court Decision(2007Do4949) is as follows: In case shareholders are granted the preemptive right to subscribe, the director doesn't breach the criminal fiduciary duty even when convertible bonds are issued at a giveaway price or an unfairly low price. On the contrary, in case convertible bonds are issued to a third party at a giveaway price or an unfairly low price, director should be punished a criminal breach of trust against the issuing corporation. The author argues that this Supreme Court Decision(2007Do4949) have two serious mistakes. One is that Supreme Court Decision doesn't discriminate breach of the criminal fiduciary duty from damage of a corporation. The other is that Supreme Court Decision doesn't discriminate damage of a corporation from damage of shareholders. This case review analyzes that these mistakes are harmful both economic criminal law and business law.s

Antioxidant and hepatoprotective effects of Korean ginseng extract GS-KG9 in a D-galactosamine-induced liver damage animal model

Yun Ho Jo,Hwan Lee,Myeong Hwan Oh,Gyeong Hee Lee,You Jin Lee,Ji Sun Lee,Min Jung Kim,Won Yong Kim,Jin Seong Kim,Dae Seok Yoo,Sang Won Cho,Seon Woo Cha,Mi Kyung Pyo 한국영양학회 2020 Nutrition Research and Practice Vol.14 No.4

BACKGROUND/OBJECTIVES: This study was designed to investigate the improvement effect of white ginseng extract (GS-KG9) on D-galactosamine (Ga1N)-induced oxidative stress and liver injury. SUBJECTS/METHODS: Sixty Sprague-Dawley rats were divided into 6 groups. Rats were orally administrated with GS-KG9 (300, 500, or 700 mg/kg) or silymarin (25 mg/kg) for 2 weeks. The rats of the GS-KG9- and silymarin-treated groups and a control group were then intraperitoneally injected Ga1N at a concentration of 650 mg/kg for 4 days. To investigate the protective effect of GS-KG9 against GalN-induced liver injury, blood liver function indicators, anti-oxidative stress indicators, and histopathological features were analyzed. RESULTS: Serum biochemical analysis indicated that GS-KG9 ameliorated the elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) in GalN-treated rats. The hepatoprotective effects of GS-KG9 involved enhancing components of the hepatic antioxidant defense system, including glutathione, glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT). In addition, GS-KG9 treatment inhibited reactive oxygen species (ROS) production induced by GalN treatment in hepatocytes and significantly increased the expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins, which are antioxidant proteins. In particular, by histological analyses bases on hematoxylin and eosin, Masson"s trichrome, α-smooth muscle actin, and transforming growth factor-β1 staining, we determined that the administration of 500 mg/kg GS-KG9 inhibited hepatic inflammation and fibrosis due to the excessive accumulation of collagen. CONCLUSIONS: These findings demonstrate that GS-KG9 improves GalN-induced liver inflammation, necrosis, and fibrosis by attenuating oxidative stress. Therefore, GS-KG9 may be considered a useful candidate in the development of a natural preventive agent against liver injury.