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.

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

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.

막증식 사구체신염으로 발현한 루푸스 신염 1례

윤신애, 이호창, 하태선 충북대학교 의과대학 충북대학교 의학연구소 2012 忠北醫大學術誌 Vol.22 No.1

전신성 홍반성 낭창(systemic lupus erythematosus, SLE)은 비정상적으로 증가한 병원성 자가 항체와 면역복합체에 의한 조직 및 세포의 손상을 특징으로 하는 자가 면역성 질환으로, 다양한 자가 항체와 면역복합체는 신장을 포함한 모든 장기를 침범할 수 있다. 신장을 침범한 전신성 홍반성 낭창은 단백뇨, 현미경적 혈뇨, 고혈압과 신기능 이상을 발현할 수 있다. 저자들은 초기 임상적으로 막증식 사 구체신염(membranoproliferative glomerulonephritis, MPGN)의 임상소견으로 발현하여, 검사 상 전신성 홍반성 낭창과 조직학적으로 MPGN 소견을 보인 여자 환아를 경험하였기에 문헌고찰과 함께 보고하는 바이다.

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

지삭의 양단이 단순고정된 화물삭도의 선로해석

신재균,최선호 영남대학교 공업기술연구소 1989 연구보고 Vol.17 No.1

A method of analyzing load-carrying ropeways is suggested in this study. Compared to to the ropeways for passengers whose tension at the one end of the main rope is given, load-carrying ropeways require different treatment because their main ropes are fixed at both ends. This difference makes the problem of analyzing load-carrying ropeways a statically indeterminate one and some iteraive solution technique seems to be inevitable. But, it is shown that this statically indeterminate problem can conceptually be reduced to a problem of solving a nonlinear algebraic equation in this study, and some numerical method such as Newton-Ropshon method can be applied successfully to solve the problem. Also, some example ropeways are analyzed after the proposed solution technique and the results are discussed.

뇌수막종에 관한 연구 : 병리조직학적, 면역조직화학적 및 중합효소연쇄반응을 중심으로

신호,임성철,이선일 대한신경외과학회 1996 Journal of Korean neurosurgical society Vol.25 No.3

Meningioma is the most common primary intracranial neoplasm that orginates from the meningothelial cells. It occurs mainly in adults, and has a female preponderance. It is classically into three main types : meningotheliomatous or syncytial type, fibrous or fibroblastic type, and transitional type. Transforming growth factor α(TGF-α) was known as a neoplastic transformer found in the neoplastic tissue of the brain rather than in normal tissue. In the neoplastic tissue, the expression of the TGF-α was more intense in the malignant rather than benign tumor, but, the expression of the TGF-α on the meningioma was not reported. Transforming growth factor-β(TGF-β) was known as a peptide which is involved in the proliferation of the mesenchymal cells and the other many physiologic processes. Tumor necrosis factor(TNF) has a selective necrotic action of the neoplastic cells without influence on normal tissues. Epidermal growth factor(EGF) and epidermal growth factor receptor(EGR) have a control effect on cellular proliferation and differentiation, and the expression of the EGR in breast cancer has a reverse correlation to the expression of the setrogen receptor(ER). The meningioma is the most common host tumor of breast cancer among the intracranial neoplasm, so presence of some estrogen receptors in the meningioma is suspected. The correlation of the estrogen receptor expression to EGR expression in the meningioma is the concern of this study. Therefore, the authors have observed the meningioma on the basis of the expression of the EG, TGF-α, TGFβ, TNF-β, EGF and EGR were more intensely positive in 2 out of 25 examined cases, especially in the vascular wall and perivascular area. TNF-β expression was weakly positive to focal area only in one case of the meningotheliomatous type. The ER expression was weakly positive to focal areas. The subtypes of meningioma expressing positively were meningotheliomatous and transitional type, which were not related to tumor aggressiveness or poor prognosis. In conclusion, ER, EGF-α, TGF-β, TNF-β, EGF and EGR were expressed in the meningioma, and it is suspected that these factors may be involved in the tumorigenesis or "host" tumor action rather than in tumor aggressiveness.