The caspase-8/Bid/cytochrome <i>c</i> axis links signals from death receptors to mitochondrial reactive oxygen species production

Kim, Wan-Sung,Lee, Kwang-Soon,Kim, Ji-Hee,Kim, Chun-Ki,Lee, Gwangsoo,Choe, Jongseon,Won, Moo-Ho,Kim, Tae-Hyoung,Jeoung, Dooil,Lee, Hansoo,Kim, Ji-Yoon,Ae Jeong, Mi,Ha, Kwon-Soo,Kwon, Young-Guen,Kim, Y PERGAMON PRESS 2017 FREE RADICAL BIOLOGY AND MEDICINE Vol.112 No.-

<P><B>Abstract</B></P> <P>Ligation of the death receptors for TNF-α, FasL, and TRAIL triggers two common pathways, caspase-dependent intrinsic apoptosis and intracellular reactive oxygen species (ROS) generation. The apoptotic pathway is well characterized; however, a signaling linker between the death receptor and ROS production has not been clearly elucidated. Here, we found that death receptor-induced ROS generation was strongly inhibited by mitochondrial complex I and II inhibitors, but not by inhibitors of NADPH oxidase, lipoxygenase, cyclooxygenase or xanthine oxidase, indicating that ROS are mostly generated by the impairment of the mitochondrial respiratory chain. ROS generation was accompanied by caspase-8 activation, Bid cleavage, and cytochrome <I>c</I> release; it was blocked in FADD- and caspase-8-deficient cells, as well as by caspase-8 knockdown and inhibitor. Moreover, Bid knockdown abrogated TNF-α- or TRAIL-induced ROS generation, whereas overexpression of truncated Bid (tBid) or knockdown of cytochrome <I>c</I> spontaneously elevated ROS production. In addition, p53-overexpressing cells accumulated intracellular ROS via cytochrome <I>c</I> release mediated by the BH3-only protein Noxa induction. In a cell-free reconstitution system, caspase-8-mediated Bid cleavage and recombinant tBid induced mitochondrial cytochrome <I>c</I> release and ROS generation, which were blocked by Bcl-xL and antioxidant enzymes. These data suggest that anti-apoptotic Bcl-2 proteins play an important role in mitochondrial ROS generation by preventing cytochrome <I>c</I> release. These data provide evidence that the FADD/caspase-8/Bid/cytochrome <I>c</I> axis is a crucial linker between death receptors and mitochondria, where they play a role in ROS generation and apoptosis.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Death receptor ligands produce mitochondrial ROS (mROS) in a caspase-8-dependent manner. </LI> <LI> mROS production requires tBid formation and cytochrome <I>c</I> release. </LI> <LI> The caspase-8/Bid/cytochrome <I>c</I> axis plays a key role in death receptor-mediated mROS generation. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

NF-κB–responsive miRNA-31-5p elicits endothelial dysfunction associated with preeclampsia via down-regulation of endothelial nitric-oxide synthase

Kim, Suji,Lee, Kyu-Sun,Choi, Seunghwan,Kim, Joohwan,Lee, Dong-Keon,Park, Minsik,Park, Wonjin,Kim, Tae-Hoon,Hwang, Jong Yun,Won, Moo-Ho,Lee, Hansoo,Ryoo, Sungwoo,Ha, Kwon-Soo,Kwon, Young-Guen,Kim, Youn American Society for Biochemistry and Molecular Bi 2018 The Journal of biological chemistry Vol.293 No.49

<P>Inflammatory cytokines, including tumor necrosis factor-α (TNFα), were elevated in patients with cardiovascular diseases and are also considered as crucial factors in the pathogenesis of preeclampsia; however, the underlying pathogenic mechanism has not been clearly elucidated. This study provides novel evidence that TNFα leads to endothelial dysfunction associated with hypertension and vascular remodeling in preeclampsia through down-regulation of endothelial nitric-oxide synthase (eNOS) by NF-κB–dependent biogenesis of microRNA (miR)-31-5p, which targets eNOS mRNA. In this study, we found that miR-31-5p was up-regulated in sera from patients with preeclampsia and in human endothelial cells treated with TNFα. TNFα-mediated induction of miR-31-5p was blocked by an NF-κB inhibitor and NF-κB p65 knockdown but not by mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase inhibitors, indicating that NF-κB is essential for biogenesis of miR-31-5p. The treatment of human endothelial cells with TNFα or miR-31-5p mimics decreased endothelial nitric-oxide synthase (eNOS) mRNA stability without affecting <I>eNOS</I> promoter activity, resulting in inhibition of eNOS expression and NO/cGMP production through blocking of the functional activity of the eNOS mRNA 3′-UTR. Moreover, TNFα and miR-31-5p mimic evoked endothelial dysfunction associated with defects in angiogenesis, trophoblastic invasion, and vasorelaxation in an <I>ex vivo</I> cultured model of human placental arterial vessels, which are typical features of preeclampsia. These results suggest that NF-κB–responsive miR-31-5p elicits endothelial dysfunction, hypertension, and vascular remodeling via post-transcriptional down-regulation of eNOS and is a molecular risk factor in the pathogenesis and development of preeclampsia.</P>

한국인 대장 선종성용종 환자에서의 MYH 유전자 변이에 대한 연구

김한수 ( Hansoo Kim ),김효종 ( Hyo Jong Kim ),지성길 ( Sung Gil Chi ),주광로 ( Gwang Ro Joo ),동석호 ( Seok Ho Dong ),김병호 ( Byung Ho Kim ),장영운 ( Young Woon Chang ),이정일 ( Jung Il Lee ),장린 ( Rin Chang ) 대한장연구학회 2005 Intestinal Research Vol.3 No.1

Background/Aims: Recently, germ-line mutation in the base-excision-repair gene MYH was identified to cause a novel autosomal recessive form of familial adenomatous polyposis (FAP). Interestingly, a striking evidence for MYH mutations within different ethnic groups has been demonstrated. We have screened 30 patients with multiple adenomatous polyps for MYH mutations to assess its prevalence and ethnic specificity in Korea. Methods: Thirty patients with multiple adenomatous polyps were examined for MYH mutations. Twenty-one men and 9 women presented at a median age of 62.3 years. The mean number of adenomas per patient was 10.0. Sixteen exonic regions and its intronic sequences were amplified by PCR and subjected to SSCP and DNA sequencing analyses. Results: None of the patients was identified to carry any truncating or sequence alterations in MYH. Our screening for the mutational regions, which were recognized from Caucasian patients or affected Indian families, also failed to detect sequence substitutions. Conclusions: Mutation in MYH may be rarely involved in the pathogenesis of multiple sporadic colorectal adenomas in Korea, although large-scale analysis will be required to clarify the presence of specific MYH variants in a subset of patients and its role for the predisposition of multiple colorectal adenomas in Korea. (Intest Res 2005;3:27-32)

60m급 파력발전 실해역 시험장 선정을 위한 제주도 차귀도 해역의 해저 지층 탐사

김한수(Hansoo Kim),김정록(Jeongrok Kim),조일형(Il-Hyoung Cho),팽동국(Dong-Guk Paeng),최종수(Jong-Su Choi) 한국해양공학회 2017 韓國海洋工學會誌 Vol.31 No.4

The purpose of this study was to investigate the sea floor using a seismic profiler in the northern part of Chagwi-do of Jeju Island in order to select the optimal location for the 60-m-class berth of a sea test bed for wave energy converters and provide basic environmental data for designing a suction anchor. The echo types of the seismic profiles were classified based on the study of Kim et al. (2016a), and the location for installing the suction anchor was selected based on a sediment thickness of more than 10 m. The physical properties of the surface sediments were determined by analyzing the sediment samples obtained from 16 grab sample points. Based on the investigation and analysis, we proposed a survey area in the North-Eastern sea as an optimum location for the 60-m-class berth where the suction anchor could be installed.

Association Between Local Government Social Expenditures and Mortality Levels in Korea

Ko, Hansoo,Kim, Jinseob,Kim, Donggil,Kim, Saerom,Park, Yukyung,Kim, Chang-Yup The Korean Society for Preventive Medicine 2013 Journal of Preventive Medicine and Public Health Vol.46 No.1

Objectives: We examined the association between social expenditures of the local government and the mortality level in Korea, 2004 to 2010. Methods: We used social expenditure data of 230 local governments during 2004 to 2010 from the Social Expenditure Database prepared by the Korean Institute for Health and Social Affairs. Fixed effect panel data regression analysis was adopted to look for associations between social expenditures and age-standardized mortality and the premature death index. Results: Social expenditures of local governments per capita was not significantly associated with standardized mortality but was associated with the premature death index (decline of 1.0 [for males] and 0.5 [for females] for each expenditure of 100 000 Korean won, i.e., approximately 100 US dollar). As an index of the voluntary effort of local governments, the self-managed project ratio was associated with a decline in the standardized mortality in females (decline of 0.4 for each increase of 1%). The share of health care was not significant. Conclusions: There were associations between social expenditures of the local government and the mortality level in Korea. In particular, social expenditures per capita were significantly associated with a decline in premature death. However, the voluntary efforts of local governments were not significantly related to the decline in premature death.

N-Terminal Modification of the Tetrapeptide Arg-Leu-Tyr-Glu, a Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) Antagonist, Improves Antitumor Activity by Increasing its Stability against Serum Peptidases

Yun, Jung-A,Kim, Joohwan,Baek, Yi-Yong,Park, Wonjin,Park, Minsik,Kim, Suji,Kim, Taesam,Choi, Seunghwan,Jeoung, Dooil,Lee, Hansoo,Won, Moo-Ho,Kim, Ji-Yoon,Ha, Kwon-Soo,Kwon, Young-Guen,Kim, Young-Myeon American Society for Pharmacology and Experimental 2019 Molecular pharmacology Vol.96 No.6

<P>The tetrapeptide Arg-Leu-Tyr-Glu (RLYE), a vascular endothelial growth factor (VEGF) receptor-2 antagonist, has been used previously either alone or in combination with chemotherapeutic drugs for treating colorectal cancer in a mouse model. We analyzed the half-life of the peptide and found that because of degradation by aminopeptidases B and N, it had a short half-life of 1.2 hours in the serum. Therefore, to increase the stability and potency of the peptide, we designed the modified peptide, N-terminally acetylated RLYE (Ac-RLYE), which had a strongly stabilized half-life of 8.8 hours in serum compared with the original parent peptide. The IC<SUB>50</SUB> value of Ac-RLYE for VEGF-A-induced endothelial cell migration decreased to approximately 37.1 pM from 89.1 pM for the parent peptide. Using a mouse xenograft tumor model, we demonstrated that Ac-RLYE was more potent than RLYE in inhibiting tumor angiogenesis and growth, improving vascular integrity and normalization through enhanced endothelial cell junctions and pericyte coverage of the tumor vasculature, and impeding the infiltration of macrophages into tumor and their polarization to the M2 phenotype. Furthermore, combined treatment of Ac-RLYE and irinotecan exhibited synergistic effects on M1-like macrophage activation and apoptosis and growth inhibition of tumor cells. These findings provide evidence that the N-terminal acetylation augments the therapeutic effect of RLYE in solid tumors via inhibition of tumor angiogenesis, improvement of tumor vessel integrity and normalization, and enhancement of the livery and efficacy of the coadministered chemotherapeutic drugs.</P><P><B>SIGNIFICANCE STATEMENT</B></P><P>The results of this study demonstrate that the N-terminal acetylation of the tetrapeptide RLYE (Ac-RLYE), a novel vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitor, significantly improves its serum stability, antiangiogenic activity, and vascular normalizing potency, resulting in enhanced therapeutic effect on solid tumors. Furthermore, the combined treatment of Ac-RLYE with the chemotherapeutic drug, irinotecan, synergistically enhanced its antitumor efficacy by improving the perfusion and delivery of the drug into the tumors and stimulating the conversion of the tumor-associated macrophages to an immunostimulatory M1-like antitumor phenotype.</P>

수중 선박소음 음향신호를 이용한 딥러닝 기반의 선박속도 추정

김범규(Bum-Kyu Kim),김한수(Hansoo Kim),김선효(Sunhyo Kim),조성호(Sungho Cho),강돈혁(Donhyug Kang),김미라(Mira Kim),장원두(Won-Du Chang) 대한전자공학회 2023 대한전자공학회 학술대회 Vol.2023 No.6

Ginsenoside Rb1 is Transformed into Rd and Rh2 by Microbacterium trichothecenolyticum

( Hansoo Kim ),( Jeong Hoon Kim ),( Phil Young Lee ),( Kwang Hee Bae ),( Sayeon Cho ),( Byoung Chul Park ),( Heung Sop Shin ),( Sung Goo Park ) 한국미생물 · 생명공학회 2013 Journal of microbiology and biotechnology Vol.23 No.12

Ginsenosides are the most important ingredient of ginseng and are known to possess many pharmacological and biological effects. Rb1, a major protopanaxadiol ginsenoside, is the most abundant ginsenoside in Panax ginseng C.A Meyer and can be hydrolyzed into more pharmaceutically potent minor ginsenosides. To identify a microorganism that is capable of converting Rb1 into other ginsenosides, we screened 12 Microbacterium spp., and M. trichothecenolyticum was identified as a likely candidate. M. trichothecenolyticum converted Rb1 into Rd and then into Rh2 based on TLC and HPLC analyses of reaction products. This biotransformation method can be easily applied for mass production of Rd and Rh2 by using Rb1.

Polymeric biomaterials for the delivery of platinum-based anticancer drugs

Kim, Jihoon,Pramanick, Swapan,Lee, Duhwan,Park, Hansoo,Kim, Won Jong The Royal Society of Chemistry 2015 Biomaterials Science Vol.3 No.7

<▼1><P>This review discusses the recent research trends in the polymeric delivery systems for platinum-based anticancer drugs.</P></▼1><▼2><P>Since cisplatin, <I>cis</I>-diamminedichloroplatinum(ii), received FDA approval for use in cancer treatment in 1978, platinum-based drugs have been one of the most widely used drugs for the treatment of tumors in testicles, ovaries, head and neck. However, there are concerns associated with the use of platinum-based anticancer drugs, owing to severe side effects and drug resistance. In order to overcome these limitations, various drug-delivery systems have been developed based on diverse organic and inorganic materials. In particular, the versatility of polymeric materials facilitates the tuning of drug-delivery systems to meet their primary goals. This review focuses on the progress made over the last five years in the application of polymeric nanoparticles for the delivery of platinum-based anticancer drugs. The present article not only describes the fundamental principles underlying the implementation of polymeric nanomaterials in platinum-based drug delivery, but also summarizes concepts and strategies employed in the development of drug-delivery systems.</P></▼2>

3D Radar Objects Tracking and Reflectivity Profiling

Kim, Yong Hyun,Lee, Hansoo,Kim, Sungshin Korean Institute of Intelligent Systems 2012 INTERNATIONAL JOURNAL of FUZZY LOGIC and INTELLIGE Vol.12 No.4

The ability to characterize feature objects from radar readings is often limited by simply looking at their still frame reflectivity, differential reflectivity and differential phase data. In many cases, time-series study of these objects' reflectivity profile is required to properly characterize features objects of interest. This paper introduces a novel technique to automatically track multiple 3D radar structures in C,S-band in real-time using Doppler radar and profile their characteristic reflectivity distribution in time series. The extraction of reflectivity profile from different radar cluster structures is done in three stages: 1. static frame (zone-linkage) clustering, 2. dynamic frame (evolution-linkage) clustering and 3. characterization of clusters through time series profile of reflectivity distribution. The two clustering schemes proposed here are applied on composite multi-layers CAPPI (Constant Altitude Plan Position Indicator) radar data which covers altitude range of 0.25 to 10 km and an area spanning over hundreds of thousands $km^2$. Discrete numerical simulations show the validity of the proposed technique and that fast and accurate profiling of time series reflectivity distribution for deformable 3D radar structures is achievable.