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>

Fluoxetine and Sertraline Attenuate Postischemic Brain Injury in Mice

Shin, Tae-Kyeong,Kang, Mi-Sun,Lee, Ho-Youn,Seo, Moo-Sang,Kim, Si-Geun,Kim, Chi-Dae,Lee, Won-Suk The Korean Society of Pharmacology 2009 The Korean Journal of Physiology & Pharmacology Vol.13 No.3

This study aimed to investigate whether selective serotonin reuptake inhibitors (SSRIs) attenuate brain injury and facilitate recovery following photothrombotic cortical ischemia in mice. Male ICR mice were anesthetized and systemically administered Rose Bengal. Permanent focal ischemia was induced in the medial frontal and somatosensory cortices by irradiating the skull with cold light laser. The animals were treated with fluoxetine or sertraline once a day for 14 d starting 1 h after ischemic insult. Treatment with fluoxetine and sertraline significantly reduced the infarct size. The Evans blue extravasation indices of the fluoxetine- and sertraline-treated groups were significantly lower than that of the vehicle group. Treatment with fluoxetine and sertraline shifted the lower limit of the mean arterial blood pressure for cerebral blood flow autoregulation toward normal, and significantly increased the expression of heme oxygenase-1 (HO-1) and hypoxia-inducible factor-1 ${\alpha}$ (HIF-1 ${\alpha}$) proteins in the ischemic region. These results suggest that SSRIs, such as fluoxetine and sertraline, facilitate recovery following photothrombotic cortical ischemia via enhancement of HO-1 and HIF-1 ${\alpha}$ proteins expression, thereby providing a benefit in therapy of cerebral ischemia.

Fluoxetine and Sertraline Attenuate Postischemic Brain Injury in Mice

Tae Kyeong Shin,Mi Sun Kang,Ho Youn Lee,Moo Sang Seo,Si Geun Kim,Chi Dae Kim,Won Suk Lee 대한생리학회-대한약리학회 2009 The Korean Journal of Physiology & Pharmacology Vol.13 No.3

This study aimed to investigate whether selective serotonin reuptake inhibitors (SSRIs) attenuate brain injury and facilitate recovery following photothrombotic cortical ischemia in mice. Male ICR mice were anesthetized and systemically administered Rose Bengal. Permanent focal ischemia was induced in the medial frontal and somatosensory cortices by irradiating the skull with cold light laser. The animals were treated with fluoxetine or sertraline once a day for 14 d starting 1 h after ischemic insult. Treatment with fluoxetine and sertraline significantly reduced the infarct size. The Evans blue extravasation indices of the fluoxetine- and sertraline-treated groups were significantly lower than that of the vehicle group. Treatment with fluoxetine and sertraline shifted the lower limit of the mean arterial blood pressure for cerebral blood flow autoregulation toward normal, and significantly increased the expression of heme oxygenase-1 (HO-1) and hypoxia-inducible factor-1Ձ (HIF-1Ձ) proteins in the ischemic region. These results suggest that SSRIs, such as fluoxetine and sertraline, facilitate recovery following photothrombotic cortical ischemia via enhancement of HO-1 and HIF-1Ձ proteins expression, thereby providing a benefit in therapy of cerebral ischemia.

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.

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

確率有限要素法을 利用한 Frame 構造物의 信賴性解析

신재철,정원석,한성호,김선훈 忠南大學校 産業技術硏究所 2002 산업기술연구논문집 Vol.17 No.1

In this paper reliability analysis using stochastic finite element method is formulated, and with its result reliability analysis is accomplished. A displacement and member force of frame structure is acquired in SFEMP(Stochastic Finite Element Method Program) using perturbation method, and then DMCSP(Direct Monte Carlo Simulation Program) is used to verify and compare previous results. With the previous two results, approximate reliability analyses of the MFOSM(Mean First Order Second Moment), AFOSM(Advanced First Order Second Moment), and MCS(Monte Carlo Simulation) including a relatively simple limit state function have accomplished and base of a safety estimate could be acquired. Finally, When the reliability analysis of a complicated structure using stochastic finite element method is accomplished, time is efficiently reduced, and the safety of a structure can be easily evaluated. Hence SFEMP may be considered an efficient tool for evaluating the structural safety and reliability of frame structure.

만성부비동염 환자에서 부비동 단순 X-선 사진과 전산화 단층(CT) 사진 소견의 비교

선동일,윤선호,신민호,서병도,양일권 釜算慶南耳鼻咽喉科學會 1993 임상이비인후과 Vol.4 No.1

대형 화재로 인한 사상자의 손상 유형과 합병증 : 동인천 라이브호프 화재를 중심으로

신중호,김재광,염석란,신종환,민순식,임용수,양혁준,이근,황성연 대한응급의학회 2001 대한응급의학회지 Vol.12 No.3

Background: High risks of fire alway exist for buildings in urban areas, especially those in downtown. Crowds, as well as more complex and larger structures, may cause more victims in the event of fire; therefore, emergency medical service plans must be established for such disastrous events. Methods: On the evening of October 30,1999, a fire broke out in downtown, Dong-Incheon Live-Hof restaurant; 56 people were killed and 76 were injured. Most of them were teenagers. We retrospectively reviewed the medical records of the victims, Results: 1) Among the 56 dead, 54 died from smoke inhalation, one from extensive burns, and one from sepsis during treatment. 2) Among the 76 injured, 70 patients suffered from smoke inhalation, 53 from burns, and 9 from several types of trauma (sprains, contusions, lacerations, abrasions, fractures, etc.). 3) Later complications were laryngeal edema, pulmonary edema, scar contracture, and hypoxic brain damage, and so forth. 4) Post traumatic stress syndrome was unexpectedly more prevalent in mildly to moderately injured survivors and witnesses than in seriously injured survivors. Conclusion: Many complications exist after a fire. Some may be resolved in time, but others may result in permanent sequelae. Early rescue, early triage, and early management during transport by emergency medical service (EMS) personnel can result in fewer complications and a lower mortality rate. Therefore, we propose the establishment of plans to be followed during various major disasters.

어휘 주석의 종류가 한국 고등학교 영어 학습자의 우연적 어휘 학습에 미치는 영향

신호선 이화여자대학교 교육대학원 2003 이화교육논총 Vol.13 No.-

Effective vocabulary learning and teaching are important because Korean high school English classes focus on reading and vocabulary is in an inseparable relation with reading. Although traditional direct vocabulary teaching focusing on form and meaning of words seem to have an immediate effect, it lacks authentic vocabulary use and results in only fragmentary knowledge. The importance of vocabulary learning in authentic situation has lead to studies that understanding meaning of vocabulary in meaningful and communicative context is effective. Unintended incidental vocabulary learning can occur naturally through reading, and many studies showed that providing marginal glosses was very effective way for incidental vocabulary learning. Therefore, this study examines the effects of marginal glosses on the incidental vocabulary learning. The subjects used for this study consisted of two hundred fifty eight second-year high school students who were divided into three groups, Korean gloss group, English gloss group, and no gloss group. These three groups read two passages; an expository text and a narrative text. They answered reading comprehension questions with the given texts, and then they submitted the texts. Next they had the first unexpected vocabulary test. A week later, the second unexpected vocabulary test which was the equivalent of the first was administered in order to examine the retention of the acquired vocabulary. Right after the second test, the vocabulary test in context was given to investigate the effect of context on recall. In addition, a questionnaire which asked the usefulness of the glosses and the attitude to hereafter use of glosses was completed. The process in which twelve learners used the glosses was investigated through think-aloud protocols and they were interviewed about their opinions toward the passages and glosses through retrospection protocols. The major results of this study are as follows. First, the results showed a significant effect of the glosses on the incidental vocabulary learning and the retention. Also the glosses had a significant effect on recall when context was given. Moreover, the Korean glosses had a more powerful effect on vocabulary learning than the English glosses. Second, the results of the questionnaire indicated that the Korean gloss group had more advantages from glosses than the English gloss group did. But both groups showed positive attitude towards hereafter use of both Korean and English glosses. The fact that the English gloss group showed significantly higher score in the attitude to the use of English glosses indicates that the experience of using English glosses had a positive effect on the learners' attitude. Third, the process of using English glosses were observed through think-aloud protocols. The learners generally made good use of English glosses and understood the meaning correctly. However the small quantity of incidental vocabulary learning was confirmed by the low score on the vocabulary test It means that giving right answers on the vocabulary test was not easy even though the subjects understood the English glosses when reading. Fourth, the interview concluded that the expository text in this study was easier to understand than the narrative because of the familiarity of the wards and that the glosses were very helpful to understand both the texts. The learners have a positive attitude to study vocabulary meaning through English, and want textbooks to have English glosses and teachers to teach them words with English meaning. They prefer English meaning with Korean meaning to English meaning only. In summary, the results of this study indicate that marginal glosses are effective not only on reading comprehension but also on vocabulary learning. This suggests that reading passages should have marginal glosses. Moreover, appropriate English glosses should be provided based on features of wards and learners' proficiency levels, considered the fact that the English gloss group and the upper level learners have a positive attitude to the use of English glosses.