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.

Heme oxygenase-1 (HO-1)/carbon monoxide (CO) axis suppresses RANKL-induced osteoclastic differentiation by inhibiting redox-sensitive NF-κB activation

( Sun-uk Bak ),( Suji Kim ),( Hae-jun Hwang ),( Jung-a Yun ),( Wan-sung Kim ),( Moo-ho Won ),( Ji-yoon Kim ),( Kwon-soo Ha ),( Young-guen Kwon ),( Young-myeong Kim ) 생화학분자생물학회(구 한국생화학분자생물학회) 2017 BMB Reports Vol.50 No.2

Heme oxygenase (HO-1) catalyzes heme to carbon monoxide (CO), biliverdin/bilirubin, and iron and is known to prevent the pathogenesis of several human diseases. We assessed the beneficial effect of heme degradation products on osteoclastogenesis induced by receptor activator of NF-κB ligand (RANKL). Treatment of RAW264.7 cells with CORM-2 (a CO donor) and bilirubin, but not with iron, decreased RANKLinduced osteoclastogenesis, with CORM-2 having a more potent anti-osteogenic effect. CORM-2 also inhibited RANKLinduced osteoclastogenesis and osteoclastic resorption activity in marrow-derived macrophages. Treatment with hemin, a HO-1 inducer, strongly inhibited RANKL-induced osteoclastogenesis in wild-type macrophages, but was ineffective in HO-1^+/-cells. CORM-2 reduced RANKL-induced NFATc1 expression by inhibiting IKK-dependent NF-κB activation and reactive oxygen species production. These results suggest that CO potently inhibits RANKL-induced osteoclastogenesis by inhibiting redox-sensitive NF-κB-mediated NFATc1 expression. Our findings indicate that HO-1/CO can act as an antiresorption agent and reduce bone loss by blocking osteoclast differentiation. [BMB Reports 2017; 50(2): 103-108]

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.

경부고속철도건설사업 성과평가

송성태(Sung Tae Song),최문규(Moon Kyu Choi),박상구(Sang Gu Park),장호환(Ho Hwan Jang),차효정(Hyo Jung Cha) 한국철도학회 2012 한국철도학회 학술발표대회논문집 Vol.2012 No.5

1992년 첫 삽을 뜨면서 시작한 경부고속철도건설사업이 2004년 4월, 1단계 개통을 한데 이어 지난 2010년 11월 완전 개통하였다. 경부고속철도 개통으로 경부축 지역의 2시간대 서비스 제공을 통한 국토의 균형발전 촉진 및 여가·관광사업 활성화, 기술발전, 환경비용 및 에너지 절감 등 긍정적인 효과를 이룬 반면, 잦은 기본계획 변경으로 인한 사업비 및 사업기간의 증가, 현실과 맞지 않은 설치기준으로 인한 과잉설계 문제 등 부정적 효과도 초래했다. 본 연구를 통해 사업추진 단계별 주요 이슈에 대해 객관적인 시각으로 문제점을 분석하고 시사점을 도출함으로써, 현재 추진하고 있는 호남고속철도와 수도권고속철도 사업에서는 시행착오를 줄이고 사업을 효율적으로 추진하는데 활용하고자 한다. Launched in 1992, the Gyeung-Bu High Speed Railway (HSR) was fully opened in November 2010 following the partial opening of the first phase in April 2004. Since the opening it has made tremendous achievements, including but not limited to, technical innovation, balanced regional development, growth of leisure and tourism industries, and savings of environmental costs and energy. On the other hand, it has brought negative effects such as increase in project time and cost by frequent changes of the basic plan and over-design based on unrealistic criteria. In this study we will analyze major issues that occurred at each stage of the Gyeong-Bu HSR project and draw implications. Thus, this study will enhance to efficiently implement the Ho-Nam and Seoul Metropolitan HSR project through minimizing possible trials and errors.

Detection of benzalkonium chloride on glass surfaces using silver nanoparticles

Nguyễn Hoàng Ly,Phuong-Dong Nguyen,Sang Jun Son,이철민,Soonmin Jang,주상우,Kyungjoo Kim,Jiseon Choi,Ye-eun Joo,Jung Il Lee 대한화학회 2022 Bulletin of the Korean Chemical Society Vol.43 No.2

Raman reporter-based surface-enhanced Raman scattering (SERS) has been used to investigate the detection of one member of a class of the cationic surfactant quaternary ammonium compounds, alkyl dimethyl benzyl ammonium chloride, also known as benzalkonium chloride (BAC). For this study, SERS was performed using silver nanoparticles (AgNPs). Density functional theory (DFT) of BAC on Ag6 clusters was introduced to estimate binding at the level of the B3LYP/LANL2DZ basis sets. As the chain length increased from n = 8 to 18, the binding energies were expected to increase by 2.1 kcal/mol. Methylene blue (MB) Raman reporter molecules were subsequently treated on BAC thin-film-covered glass surfaces. Atomic force microscopy (AFM) images were used to determine the coverage of BAC on the glass, and field-emission electron microscope (FE-SEM) images revealed the surface morphologies of the SERS substrates. A standard calibration curve was prepared to quantify BAC within a concentration range of 0.0036805 to 36?805?ppm (r2?≥?0.99), according to the BAC-correlated SERS intensities of MB Raman peaks at ~1620?cm?1 adsorbed on AgNPs. A molecular dynamics (MD) simulation supported strong adsorption of BAC on glass surfaces.

Antioxidant and hepatoprotective effects of Korean ginseng extract GS-KG9 in a D-galactosamine-induced liver damage animal model

Yun Ho Jo,Hwan Lee,Myeong Hwan Oh,Gyeong Hee Lee,You Jin Lee,Ji Sun Lee,Min Jung Kim,Won Yong Kim,Jin Seong Kim,Dae Seok Yoo,Sang Won Cho,Seon Woo Cha,Mi Kyung Pyo 한국영양학회 2020 Nutrition Research and Practice Vol.14 No.4

BACKGROUND/OBJECTIVES: This study was designed to investigate the improvement effect of white ginseng extract (GS-KG9) on D-galactosamine (Ga1N)-induced oxidative stress and liver injury. SUBJECTS/METHODS: Sixty Sprague-Dawley rats were divided into 6 groups. Rats were orally administrated with GS-KG9 (300, 500, or 700 mg/kg) or silymarin (25 mg/kg) for 2 weeks. The rats of the GS-KG9- and silymarin-treated groups and a control group were then intraperitoneally injected Ga1N at a concentration of 650 mg/kg for 4 days. To investigate the protective effect of GS-KG9 against GalN-induced liver injury, blood liver function indicators, anti-oxidative stress indicators, and histopathological features were analyzed. RESULTS: Serum biochemical analysis indicated that GS-KG9 ameliorated the elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) in GalN-treated rats. The hepatoprotective effects of GS-KG9 involved enhancing components of the hepatic antioxidant defense system, including glutathione, glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT). In addition, GS-KG9 treatment inhibited reactive oxygen species (ROS) production induced by GalN treatment in hepatocytes and significantly increased the expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins, which are antioxidant proteins. In particular, by histological analyses bases on hematoxylin and eosin, Masson"s trichrome, α-smooth muscle actin, and transforming growth factor-β1 staining, we determined that the administration of 500 mg/kg GS-KG9 inhibited hepatic inflammation and fibrosis due to the excessive accumulation of collagen. CONCLUSIONS: These findings demonstrate that GS-KG9 improves GalN-induced liver inflammation, necrosis, and fibrosis by attenuating oxidative stress. Therefore, GS-KG9 may be considered a useful candidate in the development of a natural preventive agent against liver injury.

Gliotoxin ameliorates TNBS-induced colitis through regulation of NF-kB, and up-regulation of HO-1

김상욱 ( Kim Sang Ug ),( Jay Min Oh ),( Yeon Hwa Kim ),( Jung Moo Hur ),( Kyo Sang Yoo ),( Yong Sung Kim ),( Joo Jin Yeom ),( Tae Hyeon Kim ),( Suck Chei Choi ),( Chang Duk Jun ),( Yong Ho Nah ) 대한소화기학회 2003 대한소화기학회 추계학술대회 Vol.2003 No.-

<Background & aims> During inflammation in colon, cells of the gut mucosa produce or express various inflammatory mediators, including IL-8, TNF-a and IL-1b, and intercellular adhesion molecule 1 (ICAM-1). These cytokines and chemokines have recently been

권역단위 농촌지역개발사업의 주민역량 측정을 위한 설문도구개발

리신호 ( Shin Ho Rhee ),민흥기 ( Heung Gi Min ),윤성수 ( Sung Soo Yoon ),정남수 ( Nam Su Jung ),장우석 ( Woo Seok Chang ) 한국농촌계획학회 2014 농촌계획 Vol.20 No.4

The purpose of this study was to develop survey tools for diagnosis of capacity levels in business promotion of rural residents when performing a rural development project of a regional unit. The cases of previous studies were analyzed to select community capacity indicators related to a rural development project. Five indicators were derived : social capital, consciousness of participation, community spirit, and leadership. Based on the five indicators, measurement items of various capacities were selected and 54 survey items were selected through evaluation of experts twice. The pilot tests were conducted and targeted at Jeonnam song ho-jung village and Gyeongnam Haegeumgang village to identify derived survey items. In addition, descriptive statistic analysis and reliability analysis were conducted. As a result, survey items were corrected by reducing 10 items of the total 54 items. This results showed that using this tool could help us understand capacity levels of rural residents.

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.

연잎, 연자육, 연자방 에탄올 추출물의 항염증 활성

이은주(Eun-Joo Lee),서유미(Yu-Mi Seo),김용현(Yong-Hyun Kim),정정욱(Chungwook Chung),성화정(Hwa-Jung Sung),손호용(Ho-Yong Sohn),박종이(Jong-Yi Park),김종식(Jong-Sik Kim) 한국생명과학회 2019 생명과학회지 Vol.29 No.4

연은 아시아 국가에서 음식과 약재로 널리 사용되는 재료이다. 본 연구에서는 연의 잎(leaf, NL), 자육(seed, NS), 자방(seedpod, NSP)으로부터 에탄올 추출물을 제조하고 이들의 항염증 활성과 작용기전을 규명하였다. 이들의 항염증 활성을 연구하기 위하여 LPS로 자극된 RAW 264.7 세포에서 nitric oxide (NO) 생산을 측정하였다. NL, NS, NSP는 세포 생존율에 영향을 주지 않으면서, 농도의존적으로 NO의 생산을 현저하게 저해하였으며, iNOS 및 COX-2와 같은 pro-inflammatory 중재자들의 단백질 발현을 감소시켰다. 또한, NL, NS, NSP는 MAPKs 단백질의 인신화를 감소시키고 NF-κB p65의 핵으로의 이동을 저해함으로써, 세 추출물에 의한 항염증 활성은 MAPKs 경로와 NF-κB 경로를 조절함으로써 이루어짐을 제시한다. 게다가, ROS의 생성이 세 추출물에 의해서 모두 저해되었으며, HO-1의 발현과 HO-1의 전사조절인자인 Nrf2의 핵으로의 이동이 증가되었다. 결론적으로, 이러한 연구결과는 연의 다양한 부위의 추출물인 NL, NS 그리고 NSP는 항염증 활성을 가지고 있으며, MAPKs, NF-κB, Nrf2/HO-1 등 다양한 신호경로를 통해 조절할 수 있음을 제시한다. Nelumbo nucifera, also known as sacred lotus, has mainly been used as a food throughout the Asian countries. In the present study, we prepared ethanol extracts from leaf (NL), seed (NS), and seedpod (NSP) of Nelumbo nucifera and investigated their anti-inflammatory activities in mouse macrophage RAW 264.7 cells. To evaluate the anti-inflammatory activities of NL, NS, and NSP, nitric oxide (NO) production was measured in LPS-stimulated RAW 264.7 cells. NL, NS, and NSP significantly reduced NO production in a dose-dependent manner without affecting cell viabilities. NL, NS, and NSP dramatically decreased the protein expression of pro-inflammatory genes such as iNOS and COX-2. NL, NS, and NSP also suppressed phosphorylation of MAPKs and the nuclear translocation of NF-κB p65 indicating they have their anti-inflammatory activities via regulating mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB) pathways. In addition, we analyzed the production of reactive oxygen species (ROS) by the treatment of NL, NS, and NSP. All extracts reduced ROS production in a dose-dependent manner. And also, they increased heme oxygenase-1 (HO-1) protein expression and the nuclear translocation of nuclear respiratory factor 2 (Nrf2). In conclusion, our results suggest that Nelumbo nucifera has its anti-inflammatory activity via regulating MAPKs, NF-κB, and Nrf2/HO-1 pathways.