Prediction of drug-induced immune-mediated hepatotoxicity using hepatocyte-like cells derived from human embryonic stem cells

Kim, Dong Eon,Jang, Mi-Jin,Kim, Young Ran,Lee, Joo-Young,Cho, Eun Byul,Kim, Eunha,Kim, Yeji,Kim, Mi Young,Jeong, Won-il,Kim, Seyun,Han, Yong-Mahn,Lee, Seung-Hyo Elsevier 2017 Toxicology Vol.387 No.-

<P><B>Abstract</B></P> <P>Drug-induced liver injury (DILI) is a leading cause of liver disease and a key safety factor during drug development. In addition to the initiation events of drug-specific hepatotoxicity, dysregulated immune responses have been proposed as major pathological events of DILI. Thus, there is a need for a reliable cell culture model with which to assess drug-induced immune reactions to predict hepatotoxicity for drug development. To this end, stem cell-derived hepatocytes have shown great potentials. Here we report that hepatocyte-like cells derived from human embryonic stem cells (hES-HLCs) can be used to evaluate drug-induced hepatotoxic immunological events. Treatment with acetaminophen significantly elevated the levels of inflammatory cytokines by hES-HLCs. Moreover, three human immune cell lines, Jurkat, THP-1, and NK92MI, were activated when cultured in conditioned medium obtained from acetaminophen-treated hES-HLCs. To further validate, we tested thiazolidinedione (TZD) class, antidiabetic drugs, including troglitazone withdrawn from the market because of severe idiosyncratic drug hepatotoxicity. We found that TZD drug treatment to hES-HLCs resulted in the production of pro-inflammatory cytokines and eventually associated immune cell activation. In summary, our study demonstrates for the first time the potential of hES-HLCs as an <I>in vitro</I> model system for assessment of drug-induced as well as immune-mediated hepatotoxicity.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Generation and characterization of hES-HLCs for evaluation of drug-induced immune cell-mediated hepatotoxicity. </LI> <LI> The secretion of inflammatory cytokines is highly enhanced from APAP-treated hES-HLCs. </LI> <LI> Immune cells are activated and produce pro-inflammatory cytokines by conditioned medium from hES-HLCs cultured with APAP. </LI> <LI> Hepatotoxic results in hES-HLCs are consistent with those of primary human hepatocytes. </LI> <LI> Hepatotoxic drugs such as TZD, and non-hepatotoxic drugs such as aspirin and metformin, are also validated with our drug screening system. </LI> </UL> </P>

Tetravalent dengue vaccine with Salmonella Typhimurium bacterial ghost and its immunogenicity and protection efficacy using a mouse model

Eunha Kim(Eunha Kim),John Hwa Lee(John Hwa Lee) 한국예방수의학회 2019 한국예방수의학회 학술대회자료집 Vol.2018 No.-

Chemically Homogeneous and Thermally Robust Ni_1–<i>x</i>Pt_<i>x</i>Si Film Formed Under a Non-Equilibrium Melting/Quenching Condition

Kim, Jinbum,Choi, Seongheum,Park, Taejin,Kim, Jinyong,Kim, Chulsung,Cha, Taeho,Lee, Hyangsook,Lee, Eunha,Won, Jung Yeon,Lee, Hyung-Ik,Hyun, Sangjin,Kim, Sunjung,Shin, Dongsuk,Kim, Yihwan,Kwon, Keewon American Chemical Society 2017 ACS APPLIED MATERIALS & INTERFACES Vol.9 No.1

<P>To synthesize a thermally robust Ni1-xPtxSi film suitable for ultrashallow junctions in advanced metal-oxide-semiconductor field-effect transistors, we used a continuous laser beam to carry out millisecond annealing (MSA) on a preformed Ni-rich silicide film at a-local surface temperature above 1000 degrees C while heating the substrate to initiate a phase transition. The melting and quenching process by this unique high-temperature MSA process formed a Ni1-xPtxSi film with homogeneous Pt distribution across the entire film thickness. After additional substantial thermal treatment up to 800 degrees C, the noble Ni1-xPtxSi film maintained a low-resistive phase without agglomeration and even exhibited interface flattening with the underlying Si substrate.</P>

Inositol polyphosphate multikinase is a coactivator for serum response factor-dependent induction of immediate early genes

Kim, Eunha,Tyagi, Richa,Lee, Joo-Young,Park, Jina,Kim, Young-ran,Beon, Jiyoon,Chen, Po Yu,Cha, Jiyoung Y.,Snyder, Solomon H.,Kim, Seyun National Academy of Sciences 2013 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.110 No.49

<P>Inositol polyphosphate multikinase (IPMK) is a notably pleiotropic protein. It displays both inositol phosphate kinase and phosphatidylinositol kinase catalytic activities. Noncatalytically, IPMK stabilizes the mammalian target of rapamycin complex 1 and acts as a transcriptional coactivator for CREB-binding protein/E1A binding protein p300 and tumor suppressor protein p53. Serum response factor (SRF) is a major transcription factor for a wide range of immediate early genes. We report that IPMK, in a noncatalytic role, is a transcriptional coactivator for SRF mediating the transcription of immediate early genes. Stimulation by serum of many immediate early genes is greatly reduced by IPMK deletion. IPMK stimulates expression of these genes, an influence also displayed by catalytically inactive IPMK. IPMK acts by binding directly to SRF and thereby enhancing interactions of SRF with the serum response element of diverse genes.</P>

The Expanding Significance of Inositol Polyphosphate Multikinase as a Signaling Hub

Kim, Eunha,Ahn, Hyoungjoon,Kim, Min Gyu,Lee, Haein,Kim, Seyun Korean Society for Molecular and Cellular Biology 2017 Molecules and cells Vol.40 No.5

The inositol polyphosphates are a group of multifunctional signaling metabolites whose synthesis is catalyzed by a family of inositol kinases that are evolutionarily conserved from yeast to humans. Inositol polyphosphate multikinase (IPMK) was first identified as a subunit of the arginine-responsive transcription complex in budding yeast. In addition to its role in the production of inositol tetrakis- and pentakisphosphates ($IP_4$ and $IP_5$), IPMK also exhibits phosphatidylinositol 3-kinase (PI3-kinase) activity. Through its PI3-kinase activity, IPMK activates Akt/PKB and its downstream signaling pathways. IPMK also regulates several protein targets non-catalytically via protein-protein interactions. These non-catalytic targets include cytosolic signaling factors and transcription factors in the nucleus. In this review, we highlight the many known functions of mammalian IPMK in controlling cellular signaling networks and discuss future challenges related to clarifying the unknown roles IPMK plays in physiology and disease.

Secreted protein lipocalin-2 promotes microglial M1 polarization

Jang, Eunha,Lee, Shinrye,Kim, Jong-Heon,Kim, Jae-Hong,Seo, Jung-Wan,Lee, Won-Ha,Mori, Kiyoshi,Nakao, Kazuwa,Suk, Kyoungho The Federation of American Societies for Experimen 2013 The FASEB Journal Vol.27 No.3

<P>Activated macrophages are classified into two different forms: classically activated (M1) or alternatively activated (M2) macrophages. The presence of M1/M2 phenotypic polarization has also been suggested for microglia. Here, we report that the secreted protein lipocalin 2 (LCN2) amplifies M1 polarization of activated microglia. LCN2 protein (EC<SUB>50</SUB> 1 μg/ml), but not glutathione <I>S</I>-transferase used as a control, increased the M1-related gene expression in cultured mouse microglial cells after 8–24 h. LCN2 was secreted from M1-polarized, but not M2-polarized, microglia. LCN2 inhibited phosphorylation of STAT6 in IL-4-stimulated microglia, suggesting LCN2 suppression of the canonical M2 signaling. In the lipopolysaccharide (LPS)-induced mouse neuroinflammation model, the expression of LCN2 was notably increased in microglia. Primary microglial cultures derived from LCN2-deficient mice showed a suppressed M1 response and enhanced M2 response. Mice lacking LCN2 showed a markedly reduced M1-related gene expression in microglia after LPS injection, which was consistent with the results of histological analysis. Neuroinflammation-associated impairment in motor behavior and cognitive function was also attenuated in the LCN2-deficient mice, as determined by the rotarod performance test, fatigue test, open-field test, and object recognition task. These findings suggest that LCN2 is an M1-amplifier in brain microglial cells.—Jang, E., Lee, S., Kim, J.-H., Kim, J.-H., Seo, J.-W., Lee, W.-H., Mori, K., Nakao, K., Suk, K. Secreted protein lipocalin-2 promotes microglial M1 polarization.</P>

디지털 리터러시의 인지적 영역 평가도구 개발을 위한 기초 연구

김종윤 ( Kim Jong-yun ),서수현 ( Seo Soohyun ),김인숙 ( Kim Insuk ),조병영 ( Cho Byeong-young ),김지연 ( Kim Ji-youn ),유상희 ( Ryu Sanghee ),김희동 ( Kim Heedong ),오은하 ( Oh Eunha ),옥현진 ( Ok Hyounjin ) 청람어문교육학회 2017 청람어문교육 Vol.0 No.62

이 연구는 디지털 리터러시의 인지적 영역 평가도구 개발을 위한 기초 연구로서, 평가도구의 개발을 위한 이론적 토대를 마련하는 데 주된 목적이 있다. 이를 위해 디지털 리터러시와 관련한 여러 문헌들을 먼저 검토한 뒤 디지털 리터러시의 개념을 `한 개인이 자신의 목적을 실현하기 위해 디지털 도구와 기술을 활용하여 텍스트를 탐색·이해·평가·적용하고, 새로운 텍스트를 창조하며, 사회 구성원들과 원활하게 소통할 수 있는 능력`으로 정의하였다. 이를 토대로 기존 평가도구가 디지털 리터러시를 얼마나 잘 평가하는지 검토하기 위해 8종의 기존 평가도구(CBAL, DIL, ePIRLS, ICILS, ORCA, PARCC, PISA DRA, SBA)를 평가틀의 측면, 평가 도구의 설계 및 문항 구성 방식의 측면을 중심으로 분석하였다. 분석 결과 기존 평가도구들이 디지털 리터러시의 제 측면을 제대로 평가하지 못하고 있으며, 특히 읽기 영역 평가에 치우치는 경향을 확인할 수 있었다. 평가 설계 및 문항 구성 방식은 평가도구별로 상이하였으며, 여러 측면에서 참조할 만한 요소들을 발견할 수 있었다. 각 평가도구의 장단점에 대한 분석을 토대로 디지털 리터러시 평가도구의 개선 방향으로서 시나리오 기반 평가와 근거 중심 평가 설계에 대해 제안하였다. As a preliminary exploration, this study aims to build a theoretical grounding for the development of digital literacy assessment that is particularly focused on cognitive domain. First, a comprehensive review of literature of the digital literacy was conducted to provide a theoretical lens to conceptualize digital literacy: individuals` ability to search, understand, evaluate, utilize, and create text and communicate with others by using digital tools and technologies to achieve one`s goal. Next, eight digital literacy assessments (CBAL, DIL, ePIRLS, ICILS, ORCA, PISA DRA, PARCC, SBA) were reviewed in terms of their assessment framework, design, and structure. As a result, it was found that each assessment partially measured digital literacy but failed to adequately capture the whole domain of digital literacy. Strengths and weaknesses of each assessment were also identified, analyzed, and compared. The study suggests scenario-based assessment and evidence-centered design as a useful framework for the development of digital literacy assessment.

한국어판 불공정에 대한 인식 척도의 타당화

김은하 ( Eunha Kim ),김해빈 ( Haebeen Kim ),김지윤 ( Jiyoon Kim ) 서강대학교 학생생활상담연구소 2021 人間理解 Vol.42 No.2

불공정한 세상에 대한 믿음(Belief in an unjust world: BUW)는 세상은 불공정하며 사람들은 자신이 노력한 것에 비해 그 보상을 받지 못한다는 믿음으로, 아직까지 우리나라에서는 BUW를 측정하는 척도가 없는 실정이다. 이에, 본 연구에서는 미국에서 개발되어 BUW를 측정하는 도구로써 유용성을 인정받은 “불공정에 대한 인식 척도”(Unjust Views Scale; UJVS)를 한국어로 번안 및 타당화였다. 이를 위해, 연구 표본 1을 대상으로 탐색적 요인분석과 신뢰도 분석을 실시한 결과, 원척도의 1개 문항을 삭제한 4개 문항, 단일요인이 적절한 것으로 나타났다. 다음으로, 연구표본 2를 대상으로 모형 1(BUW와 BJW의 역산 문항으로 구성된 단일요인 모형), 모형2(상위 1요인(공정에 대한 믿음)과 하위 2요인(BJW, BUW)으로 구성된 second-order 모형), 모형 3(BUW만으로 구성된 단일요인 모형)을 비교한 결과, 모형 3, 특히 수정지수를 반영한 수정된 모형 3이 가장 적합한 것으로 나타났다. 또한 수렴타당도, 준거타당도, 증분타당도를 확인한 결과, 한국어판 불공정에 대한 인식 척도(Korean Unjust Views Scale; K-UJVS)는 한국인에게 사용하기에 타당화한 도구로 확인되었다. Belief in an unjust world(BUW) refers to a belief that the world is unjust and people do not get what they deserve. The purpose of this study was to translate and validate the Unjust Views Scale (UJVS), a scale currently utilized in the U.S. to measure BUW. For this, we conducted exploratory factor analysis and reliability test, which resulted in 4 items and one factor. We also compared the fit of Model 1 (single factor structure-BJW and BUW as one dimension), Model 2 (second factor structure-BJW and BUW loading onto a latent factor of unjust world views), and Model 3(unidimensional factor structure of UJV) using confirmatory factor analysis and found that the revised Model 3 was statistically better than Model 1 and 2. The tests of convergent, concurrent and incremental validities revealed strong evidence for the validity of the Korean Unjust Views Scale.

Hepatitis E Virus Papain-Like Cysteine Protease Inhibits Type I Interferon Induction by Down-Regulating Melanoma Differentiation-Associated Gene 5

( Eunha Kim ),( Jinjong Myoung ) 한국미생물생명공학회(구 한국산업미생물학회) 2018 Journal of microbiology and biotechnology Vol.28 No.11

Upon viral infection, the host cell recognizes the invasion through a number of pattern recognition receptors. Melanoma differentiation associated gene 5 (MDA5) and retinoic acidinducible gene-I (RIG-I) recognize RNA molecules derived from invading viruses, activating down-stream signaling cascades, culminating in the induction of the type I interferon. On the other hand, viruses have evolved to evade type I interferon-mediated inhibition. Hepatitis E virus has been shown to encode a few antagonists of type I interferon and it is not surprising that viruses encode multiple mechanisms of viral evasion. In the present study, we demonstrated that HEV PCP strongly down-regulates MDA5-mediated activation of interferon β induction in a dose-dependent manner. Interestingly, MDA5 protein expression was almost completely abolished. In addition, polyinosinic polycytidylic acid (poly(I:C))- and Sendai virus-mediated activation of type I interferon responses were similarly abrogated in the presence of HEV PCP. Furthermore, HEV PCP down-regulates several molecules that play critical roles in the induction of type I IFN expression. Taken together, these data collectively suggest that HEV-encoded PCP is a strong antagonist of type I interferon.

Construction of 3-axis Flux-gate Magnetometer for Harbor Surveillance System

Eunhae Kim,Derac Son,Jin-Suk Cho,Hyun-Ju Chung 한국자기학회 2018 한국자기학회 학술연구발표회 논문개요집 Vol.2018 No.11