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Physiological/pathological ramifications of transcription factors in the unfolded protein response
Han, Jaeseok,Kaufman, Randal J. Cold Spring Harbor Laboratory Press 2017 Genes & development Vol. No.
<P>Numerous environmental, physiological, and pathological insults disrupt protein-folding homeostasis in the endoplasmic reticulum (ER), referred to as ER stress. Eukaryotic cells evolved a set of intracellular signaling pathways, collectively termed the unfolded protein response (UPR), to maintain a productive ER protein-folding environment through reprogramming gene transcription and mRNA translation. The UPR is largely dependent on transcription factors (TFs) that modulate expression of genes involved in many physiological and pathological conditions, including development, metabolism, inflammation, neurodegenerative diseases, and cancer. Here we summarize the current knowledge about these mechanisms, their impact on physiological/pathological processes, and potential therapeutic applications.</P>
ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death
Han, Jaeseok,Back, Sung Hoon,Hur, Junguk,Lin, Yu-Hsuan,Gildersleeve, Robert,Shan, Jixiu,Yuan, Celvie L.,Krokowski, Dawid,Wang, Shiyu,Hatzoglou, Maria,Kilberg, Michael S.,Sartor, Maureen A.,Kaufman, Ra Nature Publishing Group, a division of Macmillan P 2013 Nature cell biology Vol.15 No.5
Protein misfolding in the endoplasmic reticulum (ER) leads to cell death through PERK-mediated phosphorylation of eIF2α, although the mechanism is not understood. ChIP-seq and mRNA-seq of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), key transcription factors downstream of p-eIF2α, demonstrated that they interact to directly induce genes encoding protein synthesis and the unfolded protein response, but not apoptosis. Forced expression of ATF4 and CHOP increased protein synthesis and caused ATP depletion, oxidative stress and cell death. The increased protein synthesis and oxidative stress were necessary signals for cell death. We show that eIF2α-phosphorylation-attenuated protein synthesis, and not Atf4 mRNA translation, promotes cell survival. These results show that transcriptional induction through ATF4 and CHOP increases protein synthesis leading to oxidative stress and cell death. The findings suggest that limiting protein synthesis will be therapeutic for diseases caused by protein misfolding in the ER.
Han, Jaeseok,Kim, Eung-Hwi,Choi, Woohyuk,Jun, Hee-Sook WJG Press 2012 WORLD JOURNAL OF GASTROENTEROLOGY Vol.18 No.44
<P>To investigate the effect of insulin gene therapy using a glucose-responsive synthetic promoter in type 2 diabetic obese mice.</P>
심재석(Jaeseok Shim),한훈희(Hoonhee. Han),구정서(Jeongseo Koo),조정길(Jeonggil Cho),한병연(Byeongyeon Han) 한국철도학회 2016 한국철도학회 학술발표대회논문집 Vol.2016 No.10
본 연구에서는 IAT(Intra Airport Transit) 시스템 구축에 따른 차량 제작 전 설계검토를 위해 ASCE APM 의 구조 설계 기준 하에 차량의 구조 및 피로분석을 수행하였다. 구조건전성 평가를 위해 최대운영하중 및 일반운영하중을 고려하여 총 12 가지의 하중조건을 적용하였다. 해석결과 최대운영하중조건에서는 압축하중 조건이 안전율을 적용 후 186.2[MPa]로 가장 큰 결과 값을 얻었고 항복강도 허용기준 460[MPa] 이내에 만족 하는 것을 확인 하였다. 그 외 조건에서도 항복강도 허용기준에서 모두 만족하는 것을 확인했다. 일반운영하중조건에서는 ASCE APM 규정과 ERRI B12/RP17 규정을 적용 후 피로평가를 실시한 결과 최대 응력이 소재 피로강도의 0.75 배 이하로 만족하고 무한 수명 내로 만족하는 것을 확인하였다. 따라서 차량 제작 전 설계 검토를 위한 구조 및 피로분석에서 모두 기준 내에 만족하는 것을 확인하였다. In the study, we conducted analysis of structure and fatigue with a structural design standard of ASCE APM to review a design before making a railway vehicle for establishing IAT(Intra Airport Transit) system. We have conducted the tests under 12 load conditions considering maximum and normal operating load to evaluate structural stability of it. Based on the results, in maximum operating loads, we got 186.2 [MPa] which is the highest result value with the application of a safety factor of a compression load. This satisfies the criteria of yield strength which is less than 450 [MPa], as well as the criteria for the other loads. In normal operating loads, maximum stress satisfied a criteria which are 0.75 times less than fatigue strength of the material and within Infinite fatigue life after applying ASCE APM and ERRI B12/RP17 standards.
Roles of Toll-Like Receptors in Allogeneic Islet Transplantation
Ro, Han,Hong, Juho,Kim, Beom Seok,Lee, Eun Won,Kim, Myung-Gyu,Han, Kyu Hyun,Yeom, Hye-Jung,Lee, Eun Mi,Jeong, Jong Cheol,Oh, Kook-Hwan,Ahn, Curie,Yang, Jaeseok Lippincott Williams Wilkins, Inc. 2012 Transplantation Vol.94 No.10
BACKGROUND: Toll-like receptors (TLRs) are involved in the rejection of solid organ allografts. However, the roles of TLRs in islets are still controversial. We investigated the roles of TLRs in donor islets together with those in recipients in allogeneic islet transplantation. METHODS: To assess the roles of TLRs in either donor islets or recipients, allogeneic islet transplantation was performed using myeloid differentiation factor 88 (MyD88)-knockout (KO), TLR4-KO, or Toll/interleukin-1 receptor domain-containing adaptor-inducing interferon-&bgr; (TRIF)-KO mice. RESULTS: Both polyriboinosinic polyribocytidylic acid and lipopolysaccharide (LPS) stimulation induced the mRNA expression of regulated and normal T cell expressed and secreted, interferon-&ggr;–inducible protein-10, monocyte chemotactic protein-1, interleukin-8, and inducible nitric oxide synthase in murine islets, whereas the induction was attenuated in TRIF-KO, interferon-&bgr; promoter stimulator-1-KO, and TLR4-KO mice. When islets from MyD88-KO, TLR4-KO, or TRIF-KO C57BL/6 mice were transplanted to BALB/c recipients, graft survival was not better than that of wild-type (WT) islets. However, the survival of the MyD88-KO islet allograft was significantly prolonged when combined with anti-CD40L. In parallel, LPS stimulation in donor islets interfered with anti-CD40L blockade-mediated long-term survival of islet allografts in TLR4-KO recipients. LPS stimulation increased the perigraft infiltration of both T cells and macrophages. Then again, when islets from WT BALB/c mice were transplanted to MyD88-KO, TRIF-KO, or WT C57BL/6 mice, there was no difference in graft survival, although some of the MyD88-KO recipients obtained long-term graft survival. However, anti-CD40L prolonged graft survival significantly in MyD88-KO recipients. The absence of MyD88 in either donors or recipients decreased the perigraft infiltration of inflammatory cells when combined with anti-CD40L. CONCLUSIONS: TLRs in both donor islets and recipients are involved in islet allograft rejection.
Roles of Islet Toll-Like Receptors in Pig to Mouse Islet Xenotransplantation
Ro, Han,Lee, Eun Won,Hong, Joo Ho,Han, Kyu Hyun,Yeom, Hye-Jung,Kim, Hwa Jung,Kim, Myung-Gyu,Jung, Hye Seung,Oh, Kook-Hwan,Park, Kyong Soo,Ahn, Curie,Yang, Jaeseok SAGE Publications 2013 Cell transplantation Vol.22 No.9
<P>Although innate immunity plays important roles in xenograft rejection, there have been few studies on the role of toll-like receptors (TLRs) in xenotransplantation. Furthermore, most studies focused on the recipient's TLRs. Therefore, we investigated whether TLRs in porcine islets can contribute to islet xenograft rejection. Adult porcine islets were isolated and stimulated by polyinosinic/polycytidylic acid (poly I:C) or lipopolysaccharide (LPS). Both poly I:C and LPS stimulation in porcine islets induced expression of chemokines (RANTES, MCP-1, IP-10, and IL-8), cytokines (IL-6 and type I interferons), and adhesion molecules (VCAM-1 and ICAM-1). Porcine islet supernatants stimulated by TLR agonists induced chemotaxis of human leukocytes. They also induced procoagulant activation (tissue factor and fgl-2). However, TLR stimulation did not influence insulin secretion. When porcine MyD88 was knocked down using shRNA lentivirus, TLR-mediated induction of proinflammatory mediators and procoagulants was attenuated. When LPS was injected to MyD88 or TLR4 knockout mice after porcine islet transplantation, LPS stimulation on donor islets interfered with islet xenograft tolerance induction by anti-CD154 antibodies. Inflammatory cell infiltration and expression of proinflammatory chemokines and cytokines in islet xenografts also increased. In conclusion, TLR activation in porcine islets induced both a proinflammatory and procoagulant response and thereby contributed to xenograft rejection.</P>
Han, HyukSu,Lee, Hanchan,Lim, Jiun,Kim, Kang Min,Hong, Yu-Rim,Lee, Jaeseok,Forrester, Jennifer,Ryu, Jeong Ho,Mhin, Sungwook Elsevier 2017 CERAMICS INTERNATIONAL Vol.43 No.18
<P><B>Abstract</B></P> <P>(Ni,Co,Mn)O<SUB>4</SUB> (NMC) oxides were prepared by conventional sintering (CS) and spark plasma sintering (SPS) using micro and nanopowders. Small hoping polaron theory was used in order to investigate effect of processing routes on electrical properties of NMC oxides as negative temperature coefficient (NTC) thermistors. Also, X-ray diffraction (XRD), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS) techniques were utilized to analyze compositional and structural effects on the electrical properties of NMC compounds. Hopping conduction in NMC prepared by SPS and CS using nanopowder occurs via variable range hopping (VRH) mechanism, however conduction in NMC prepared by CS using micropowder follows nearest neighboring hopping (NNH) mode. Hopping distance and activation energy for the VRH mode were calculated using corresponding physical model.</P>