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      • 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.

      • KCI등재후보

        Adenovirus-mediated heme oxygenase-1 gene transfer to neonatal porcine islet-like cluster cells: the effects on gene expression and protection from cell stress

        염혜정,Han Ro,Sol Ji Park,Ju Ho Hong,Bumrae Cho,김화정,Sung Joo Kim,황종익,이병천,안규리,양재석 한국바이오칩학회 2012 BioChip Journal Vol.6 No.1

        Porcine islet xenotransplantation is a promising strategy for the treatment of diabetes that overcomes donor shortages. However, islet xenografts are susceptible to oxidative stress and apoptosis. Heme oxygenase-1 (HO-1) has been shown to protect cells from oxidative stress, apoptosis and inflammation. Here, we investigated whether introduction of human HO-1 (hHO-1) into neonatal porcine islet-like cell clusters (NPCCs) can induce beneficial transcriptional changes in NPCCs against cellular stress. NPCCs were transduced with either adenovirus-HO-1 (Ad-HO-1) or control adenovirus-GFP (Ad-GFP). After treatment with hydrogen peroxide (H2O2) for 24 hours, nitrite oxide (NO) production assays were performed to detect oxidative stress. Microarray analysis was performed using a pig oligonucleotide 44 K gene chip. We profiled transcriptional changes to apoptosis, oxidant and inflammatory genes, and real-time PCR analysis was also performed to confirm the microarray results. Survival of NPCCs after treatment with H2O2 was significantly higher in the Ad-HO-1 group (p⁄0.001), and NO production also decreased in the Ad-HO-1 group (p⁄0.01). The microarray results showed that the expression of pro-apoptosis genes such as CASP3, CASP7, CASP10, CIDE-B and CIDE-C was significantly decreased in the Ad-HO-1 virus group (CASP10; p⁄0.05, CASP3, CIDE-C; p⁄0.01, CASP7, CIDE-B; p⁄0.001). We also found that the expression of oxidative stresses genes including COX1, COX2, CYB5A, SDHD and NOS2 was decreased, and that the anti-oxidant genes Gpx1 and SOD2 were increased in the Ad-HO-1 group (NOS2; p⁄0.05, COXI, COX2, CYB5A, SDHD, SOD2, GPX1; p⁄0.001). However, inflammatory gene expression was not significantly changed. Realtime PCR analysis confirmed the results of the microarray analysis. These results shed light on the underlying mechanisms of the protective effects of hHO-1 on porcine islets from cellular stresses and suggest that hHO-1 could be a promising target gene for the production of transgenic pigs that confer improved islet xenograft survival.

      • KCI등재

        Synergistic Renoprotective Effect of Melatonin and Zileuton by Inhibition of Ferroptosis via the AKT/mTOR/NRF2 Signaling in Kidney Injury and Fibrosis

        Jung Kyung Hee,Kim Sang Eun,Go Han Gyeol,Lee Yun Ji,Park Min Seok,Ko Soyeon,Han Beom Seok,Yoon Young-Chan,Cho Ye Jin,Lee Pureunchowon,Lee Sang-Ho,Kim Kipyo,Hong Soon-Sun 한국응용약물학회 2023 Biomolecules & Therapeutics(구 응용약물학회지) Vol.31 No.6

        According to recent evidence, ferroptosis is a major cell death mechanism in the pathogenesis of kidney injury and fibrosis. Despite the renoprotective effects of classical ferroptosis inhibitors, therapeutic approaches targeting kidney ferroptosis remain limited. In this study, we assessed the renoprotective effects of melatonin and zileuton as a novel therapeutic strategy against ferroptosis-mediated kidney injury and fibrosis. First, we identified RSL3-induced ferroptosis in renal tubular epithelial HK-2 and HKC-8 cells. Lipid peroxidation and cell death induced by RSL3 were synergistically mitigated by the combination of melatonin and zileuton. Combination treatment significantly downregulated the expression of ferroptosis-associated proteins, 4-HNE and HO-1, and upregulated the expression of GPX4. The expression levels of p-AKT and p-mTOR also increased, in addition to that of NRF2 in renal tubular epithelial cells. When melatonin (20 mg/kg) and zileuton (20 mg/kg) were administered to a unilateral ureteral obstruction (UUO) mouse model, the combination significantly reduced tubular injury and fibrosis by decreasing the expression of profibrotic markers, such as α-SMA and fibronectin. More importantly, the combination ameliorated the increase in 4-HNE levels and decreased GPX4 expression in UUO mice. Overall, the combination of melatonin and zileuton was found to effectively ameliorate ferroptosis-related kidney injury by upregulating the AKT/mTOR/ NRF2 signaling pathway, suggesting a promising therapeutic strategy for protection against ferroptosis-mediated kidney injury and fibrosis.

      • SCISCIESCOPUS

        Morin exerts cytoprotective effects against oxidative stress in C2C12 myoblasts via the upregulation of Nrf2-dependent HO-1 expression and the activation of the ERK pathway

        Lee, Moon Hee,Han, Min Ho,Lee, Dae-Sung,Park, Cheol,Hong, Su-Hyun,Kim, Gi-Young,Hong, Sang Hoon,Song, Kyoung Seob,Choi, Il-Whan,Cha, Hee-Jae,Choi, Yung Hyun UNKNOWN 2017 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE Vol.39 No.2

        <P>In the present study, we investigated the cytoprotective efficacy of morin, a natural flavonoid, against oxidative stress and elucidated the underlying mechanisms in C2C12 myoblasts. Our results indicated that morin treatment prior to hydrogen peroxide (H2O2) exposure significantly increased cell viability and prevented the generation of reactive oxygen species. H2O2-induced comet-like DNA formation and gamma H2AX phosphorylation were also markedly suppressed by morin with a parallel inhibition of apoptosis in C2C12 myoblasts, suggesting that morin prevented H2O2-induced cellular DNA damage. Furthermore, morin markedly enhanced the expression of heme oxygenase-1 (HO-1) associated with the induction and phosphorylation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and the inhibition of Kelch-like ECH-associated protein 1 (Keapl) expression. Notably, these events were eliminated by transient transfection with Nrf2-specific small interfering RNA. Additional experiments demonstrated that the activation of the Nrf2/HO-1 pathway by morin was mediated by the extracellular signal-regulated kinase (ERK) signaling cascade. This phenomenon was confirmed with suppressed Nrf2 phosphorylation and consequently diminished HO-1 expression in cells treated with a pharmacological inhibitor of ERK. Collectively, these results demonstrated that morin augments the cellular antioxidant defense capacity through the activation of Nrf2/HO-1 signaling, which involves the activation of the ERK pathway, thereby protecting C2C12 myoblasts from H2O2,-induced oxidative cytotoxicity.</P>

      • LPS로 유도된 Human Dental Pulp Cells에서 Schisandrin C 의 항염증 효과

        Jyoti Shrestha Takanche,Sang Won Lee,Yae Jin Kim,Young Hee Lee,Jeong Seok Kim,Ji Eun Kim,Ho Keun Yi,Sin Hee Han 한국약용작물학회 2016 한국약용작물학술대회 발표집 Vol.2016 No.10

        Background : Tooth vitality is reflected by the health of dental pulp. Schisandrin C is a natural compound extracted from the fruit of Schisandra chinensis which has anti-inflammatory and anti-oxidant properties. The role of Schisandrin C on human dental pulp cells (HDPCs) has not been studied yet. This study examined the properties of Schisandrin C as an anti-inflammatory and anti-oxidant compound, and whether its characteristics promote mitochondrial biogenesis in HDPCs. Methods and Results : HDPCs were extracted from fresh third molars and cultured. Reactive oxidative stress (ROS) and nitric oxide (NO) formation were analyzed by a Muse cell analyzer. Western blotting and gelatin zymography were used to identify the presence of anti-oxidants, as well as inflammatory and mitochondrial biogenesis. Confocal microscopy was used for the detection of mitochondrial activity. Schisandrin C inhibited lipopolysaccharide (LPS)-stimulated inflammatory molecules; intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), matrix metalloproteinase-2 and -9 (MMP-2/9), NO production, ROS formation and the mitogen-activated protein (MAPK) pathway through minimizing the nuclear factor kappa B (NF-kB) translocation. Schisandrin C increased the expression of superoxide dismutase (SOD) enzymes as well as heme oxygenase-1 (HO-1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) through the phosphorylated-protein kinase B (p-AKT) and nuclear factor erythroid 2-related factor-2 (Nrf-2) pathways. The anti-inflammatory and anti-oxidant properties of Schisandrin C promoted mitochondrial biogenesis. Conclusions : These results suggest that Schisandrin C may be used as an anti-inflammatory compound to reduce oral inflammation such as pulpitis.

      • KCI등재

        환경기술과 정보기술 기반의 미래도시 공간 메커니즘과 알고리즘 분석

        한주형(Ju-Hyung Han),이상호(Sang-Ho Lee) 한국산학기술학회 2017 한국산학기술학회논문지 Vol.18 No.3

        본 연구는 정보기술과 환경기술의 미래도시 메커니즘(Mechanism) 구조와 그에 따른 알고리즘 분석을 통해 새로운 도시의 공간을 창출하는데 목표가 있다. 본 연구의 결과는 다음과 같다. 첫째, 환경과 정보기술의 개발트렌드는 친환경개발, 에너지개발, 에너지 절감기술 개발, 광역네트워크 개발 등 4가지 유형으로 분류 할 수 있다. 둘째, 사례 상암DMC는 한국전쟁부터 1978년까지 친환경과 환경 보호적 측면에서 개발이 진행되었다. 광역네트워크 개발은 1990년부터 2000년 사이에 급속하게 진화되었다. 그러나 2010년 이후 도시공간은 다시 환경과 정보의 융합에 의해 공간이 개발되고 있다. 상암DMC의 과거 개발 트렌드는 개인적인 환경기술 개발이 중심이 되었다. 현재에는 공공의 정보기술 중심으로 추진되고 있으나 일부는 환경을 중심으로 하는 준 융합개발의 트렌드를 갖고 있다. 그러나, 미래시대의 융합은 통합적 융합개발이 될 것이라 예측한다. 셋째, 메커니즘 구조는 생성, 소멸 그리고 융합과정에 의해 발전된다. 그 생성은 불충분한 부분으로부터 보충화 될 것이다. 소멸은 불충분한 부분의 융합과정에 의해서 함축화 될 것이다. 그리고 그러한 융합은 생성과 소멸의 기준이 될 것이다. 결국 새로운 창조 도시공간은 환경과 정보기술 중심의 메커니즘 기호화 패턴 구조에 의해 계속해서 형성 될 것이다. This study aims to create a new urban space through mechanism structure and algorism analysis between IT and ET. The results are as follows. First, the development trends of ET·IT are classified into 4 types, "Eco-Friendly Development", "Energy Production Technology Development", "Energy Saving Technology Development" and "Wide Area IT Network Development", which are found to be constantly evolving. Second, Sang-Am DMC developed through the environmentally protective and eco-friendly aspects of ET from the Korean War to 1978. Wide area IT networks developed rapidly from 1990 to 2000. However, in 2010, urban spaces began to develop by the fusion of the Environment and Information. The fusion of Environment and Information in the development trends in the past is referred to as "Individual Development", that in the present is referred to as "Semi-fusion Development" and that in the future will be referred to as "Total Fusion Development". Third, the mechanism structure of DMC has evolved through creation, extinction and fusion processes. The creation process will serve to supplement the insufficiencies of the existing systems, the extinction process will be the compactification of the fusion process, and the fusion process will be the standard for creation and extinction. Finally, the future of new innovative urban and architectural spaces will be forged by the mechanism symbolization patterns of IT·ET.

      • KCI등재

        해저터널 구난역 플랫폼 화재연기확산 방지를 위한 에어커튼 시스템 차연성능 시뮬레이션 연구

        박상헌,안승주,한상주,유용호,Park, Sang-Heon,An, Jung-Ju,Han, Sang-Ju,Yoo, Yong-Ho 한국터널지하공간학회 2015 한국터널지하공간학회논문집 Vol.17 No.3

        본 연구는 국내에서 계획하고 있는 호남-제주간 초장대 해저터널에서 철도차량의 화재 발생시 구난역 (Rescue Station)에 정차후 대피자의 안전한 대피경로를 확보하고 플랫폼 내부에 연기가 유입되는 것을 방지하기 위해 구난역 플랫폼과 화재열차 사이에 에어커튼 시스템(Air curtain system)을 설치하여, 15MW급 화재연기에 대한 차단성능 및 최적화방안을 도출하기 위해 다양한 시뮬레이션을 수행하였다. 시뮬레이션 결과, 모든 CASE에서 15 MW급 화재강도에 발생되는 연기에서도 효과적인 차연성능을 발휘하였으며, CASE1(화재열차 방향으로 15도 분사)와 CASE5(화재열차 방향으로 15도 분사 + 가압송풍)가 구난역 플랫폼 내부에 CO가스 유입이 가장 적은 것으로 도출하였다. 이러한 결과를 통하여 에어커튼 시스템은 초장대 해저터널 구난역에 화재시 플랫폼에 화재연기가 유입되지 않고 안전한 대피 경로를 확보하여 대피자가 서비스 터널로 안전하게 대피하여 인명피해를 최소화 할 수 있는 방재시설로서 활용되기를 기대한다. This study introduce that we studied optimization and possibility of smoke spread prevention with air-curtain system in undersea tunnel named from Ho-Nam to Jeju line in domestic if a fire break out in train. To verify performance, air-curtain system is installed between rescue station platform and each door of passenger car to provide safety route to evacuator and we studied simulation model of various cases about 15 MW fire severity considering domestic specifications. As a result we verified the fact that CASE1(air jet with 15degree toward passenger car) and CASE 5 (air jet with 15degree toward passenger car and pressure air blast from cross passage) is best Smoke Spread Prevention and less inflow carbon monoxide. Through above results, we expect that air-curtain system is one of the facilities for fire safety and provide us safety platform route in undersea tunnel.

      • SCIEKCI등재

        Phosphodiesterase inhibitor improves renal tubulointerstitial Hypoxia of the Diabetic rat Kidney

        ( Hui Kyoung Sun ),( Yun Mi Lee ),( Kum Hyun Han ),( Han Seong Kim ),( Seon Ho Ahn ),( Sang Youb Han ) 대한내과학회 2012 The Korean Journal of Internal Medicine Vol.27 No.2

        Background/Aims: Renal hypoxia is involved in the pathogenesis of diabetic nephropathy. Pentoxifyllin (PTX), a nonselective phosphodiesterase inhibitor, is used to attenuate peripheral vascular diseases. To determine whether PTX can improve renal hypoxia, we investigated its effect in the streptozocin (STZ)-induced diabetic kidney. Methods: PTX (40 mg/kg, PO) was administered to STZ-induced diabetic rats for 8 weeks. To determine tissue hypoxia, we examined hypoxic inducible factor-1α (HIF-1α), heme oxygenase-1 (HO-1), vascular endothelial growth factor (VEGF), and glucose transporter-1 (GLUT-1) levels. We also tested the effect of PTX on HIF-1α in renal tubule cells. Results: PTX reduced the increased protein creatinine ratio in diabetic rats at 8 weeks. HIF-1α, VEGF, and GLUT-1 mRNA expression increased significantly, and the expression of HO-1 also tended to increase in diabetic rats. PTX significantly decreased mRNA expression of HIF-1α and VEGF at 4 and 8 weeks, and decreased HO-1 and GLUT-1 at 4 weeks. The expression of HIF-1α protein was significantly increased at 4 and 8 weeks in tubules in the diabetic rat kidney. PTX tended to decrease HIF-1α protein expression at 8 weeks. To examine whether PTX had a direct effect on renal tubules, normal rat kidney cells were stimulated with CoCl2 (100 μM), which enhanced HIF-1α mRNA and protein levels under low glucose conditions (5.5 mM). Their expressions were similar even after high glucose (30 mM) treatment. PTX had no effect on HIF-1α expression. Conclusions: PTX attenuates tubular hypoxia in the diabetic kidney.

      • Antioxidant and cytoprotective effects of morin against hydrogen peroxide-induced oxidative stress are associated with the induction of Nrf-2-mediated HO-1 expression in V79-4 Chinese hamster lung fibroblasts

        Lee, Moon Hee,Cha, Hee-Jae,Choi, Eun Ok,Han, Min Ho,Kim, Sung Ok,Kim, Gi-Young,Hong, Su Hyun,Park, Cheol,Moon, Sung-Kwon,Jeong, Soon-Jeong,Jeong, Moon-Jin,Kim, Wun-Jae,Choi, Yung Hyun Spandidos Publications 2017 International journal of molecular medicine Vol.39 No.3

        <P>Natural phytochemicals of plant origin, including flavonoids, have been found to be potent antioxidants providing beneficial effects against oxidative stress-related diseases. The present study was carried out to investigate the antioxidant properties of morin, a flavonoid originally isolated from the flowering plants of the Moraceae family. Superoxide dismutase (SOD)-like activity and 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(center dot+)) radical scavenging activity were determined. We also investigated the cytoprotective effects of morin against hydrogen peroxide (H2O2)-induced DNA damage and apoptosis in V79-4 Chinese hamster lung fibroblasts. Our results demonstrated that morin had strong scavenging effects against ABTS' radicals with enhanced SOD activity, which varied in a dose-dependent manner. Morin was found to reduce H2O2-induced intracellular reactive oxygen species generation and nuclear DNA damage, and it recovered cell viability damaged by H2O2 via inhibition of mitochondrial dysfunction-mediated apoptosis. Notably, the treatment of V79-4 cells with morin markedly enhanced the expression of heme oxygenase-1 (HO-1) but not quinone oxidoreductase-1, which was associated with the increased expression and phosphorylation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and the downregulation of Kelch-like ECH-associated protein 1 expression. Based on our findings, we conclude that morin effectively ameliorated oxidative stress-induced DNA damage through intrinsic free radical scavenging activity and activation of the Nrf2/HO-1 pathway.</P>

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