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        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.

      • SCISCIESCOPUS

        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>

      • SCIESCOPUSKCI등재

        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.

      • KCI등재
      • KCI등재

        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

        Objective : The water extract of Chilgi-tang (CGT) has been traditionally used in treatment of heart diseases caused by stress in Oriental Medicine. However, little is known about the mechanism by which CGT rescues neuronal cells from injury damage. Therefore, this study was designed to evaluate the protective effects of CGT on Neuro-2A cells by glucose deprivation-induced cell death. Methods : We investigated how cell death induced by glucose deprivation was associated with increased reactive oxygen species (ROS) generation. Result : The CGT treatment prior to glucose deprivation insult significantly reduced the number of cell deaths and the glucose deprivation-induced increase in ROS. Nitric oxide (NO) was also attenuated by CGT treatment. In addition, we demonstrated that the anti-cell death effect of CGT was blocked by heme oxygenase-1 (HO-1) activation. Finally, pretreatment of cells with a hemin, HO-1 inducer, reduced glucose deprivation-induced cell death. In contrast, pretreatment of cells with a ZnPP, HO-1 activity inhibitor, attenuated CGT-induced inhibition of cell death. Conclusions : These findings indicate that ROS plays an important role in glucose deprivation-induced cell death and that CGT may prevent glucose deprivation-induced cell death by inhibiting the ROS generation through HO-1 activation in Neuro-2A cells.

      • SCIESCOPUSKCI등재

        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

        '스콜라' 이용 시 소속기관이 구독 중이 아닌 경우, 오후 4시부터 익일 오전 7시까지 원문보기가 가능합니다.

        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.

      • 丹參飮이 實驗動物의 心血管係에 미치는 影響

        申善澔,李基商,文病淳 圓光大學校 韓醫學硏究所 1995 원광한의학 Vol.5 No.1

        The present experiment was desinged to investigate the effects of Dansamyeum water extracts on the Cardivascular System in the Experimental Animals. Thus, the changes of blood pressure and heart rate were measured after oral administration. Measurments of Mortality rate were observed for measuring the effects of Dansamyeum water extract. Dansamyeum water extracts against pulmonary thromboembolism induced by collagen the mixture 90.1㎖/10g, 2㎖/㎏ B.W) plus serotonin(5㎎/㎏ B.W) in mouse. The effect of Dansamyeum water extract was examined by observing the change of collagen-induced platelet aggregation coagulation activity, ex vivo and in vitro fibrinolytic activity of euglobulin fraction in rats. The results were summarized as followings. 1. Dansamyeum dropped the blood pressure in spontaneous hypertensive rat. 2. The drug increased the auricular blood flow in rabbit. 3. The drug relaxed the artery contraction by pretreated norepinephrine in rat. 4. The drug inhibited the death rate of mouse which were led to thromboembolism by serotonin and collagen. 5. The drug inhibited the platelet aggregation in rat. 6. The drug prolonged the prothrombin time and activated partial thromboplastin time on the test of plasma coagulation factor activity in rat, but was not valuable. 7. The drug increased the antithrombin activity in rat and the fibrinogen lyses time was reduced and lyses area was increased. 8. Dansamyeum reduced fibrinogen lyses time of rat in vitro assay. According to the above mentioned results, Dansamyium increased the blood flow and dropped the blood pressure by the dilation of blood vessel. And the drug presented the antithrombin acivity, inhibited the platelet aggregation.

      • 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.

      • 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.

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