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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.
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.
신장이식 환자에서 HCMV 항원혈증 검사의 임상적 유용성
김탁,성흥섭,박관태,김송철,김성한,최상호,김양수,우준희,박수길,한덕종,이상오 대한감염학회 2009 감염과 화학요법 Vol.41 No.2
Background : This study was performed to determine the cut-off value and the predictability of symptomatic human cytomegalovirus (HCMV) infection according to the peak value of HCMV antigenemia assay in kidney transplant recipients. Materials and Methods : We reviewed the results of HCMV antigenemia assay (Chemicon, CA, USA) in patients who received kidney transplantation at our institution from May 2003 through May 2008, and investigated the existence and the type of HCMV infection by the medical record review. Patients who underwent the test only once during the episode or those who received ganciclovir for more than 48hrs before the test were excluded. The receiver-operator characteristic curve was drawn and the point showing maximum likelihood ratio (LR) was chosen as the cut-off value of symptomatic HCMV infection. Results : A total of 689 episodes were screened and 134 episodes were enrolled. Thirty-three (24.6%) episodes were symptomatic HCMV infection, 23 (17.2%) episodes were associated with HCMV syndrome, and 10 (7.5%) episodes were tissue-invasive diseases. The maximum LR was 7.5 (95% confidence interval, 4.014.2) and the cut-off value was 29.5 cells/200,000 WBC. The sensitivity, specificity, Positive predictive value, and negative predictive value were 66.7%, 91.1%, 71.0%, and 89.3%, respectively. Conclusions : The cut-off value of symptomatic HCMV infection by the peak value of HCMV antigenemia assay in our study was similar with previous results, although the sensitivity was relatively low.
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>
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.
서울의 Penicillinase Producing Neisseria gonorrhoeae 발생빈도(1998)
김재홍,김준호,반재용,이정우,황성주,정준규,정성태,강진문,조흔정,홍창의,정혜신,이한승,김이선,이봉길,이종호,선영우,한기덕,윤성필,이성훈,안종성,박석범,문승현,조항래,김형섭,류지호,황재영,박준홍,손상욱 한양대학교 의과대학 2001 한양의대 학술지 Vol.21 No.1
In recent years, gonorrhea has been pandemic and remains one of the most common STDs in the world, especially in developing countries. For the detection of a more effective therapeutic regimen and assessing the prevalence of Penicillinase Producing Neisseria gonorrhoeae(PPNG), we have been trying to study the patients who have visited the Venereal Disease Clinic of Choong-Ku Public Health Center in Seoul since 1980 by menas of the chromogenic cephalosporin method. In 1998, 93 strians of N. genorrhoeae were isolated, among which 60(64.5%) were PPNG. The prevalence of PPNG in Seoul, which had been decreased to 39% in 1996 after a peak of 74.3% in 1993, is increased to 64.5% in 1998.
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.
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>