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SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation

Signal Transduction and Targeted Therapy 2024年第6期9卷 2702-2715页

作者： Hye Jin Shin Wooseong Lee Keun Bon Ku Gun Young Yoon Hyun-Woo Moon Chonsaeng Kim Mi-Hwa Kim Yoon-Sun Yi Sangmi Jun Bum-Tae Kim Jong-Won Oh Aleem Siddiqui Seong-Jun Kim Department of Convergent Research of Emerging Virus Infection Korea Research Institute of Chemical TechnologyDaejeon 34114Republic of Korea Gyeongnam Biohealth Research Center Gyeongnam Branch InstituteKorea Institute of ToxicologyJinju 52834Republic of Korea Center for Research Equipment Korea Basic Science InstituteCheongjuChungcheongbuk-do 28119Republic of Korea Department of Biotechnology Yonsei UniversitySeoul 03722Republic of Korea Division of Infectious Diseases School of MedicineUniversity of CaliforniaSan DiegoLa JollaCA 92093USA Present address:Department of Microbiology Chungnam National University School of MedicineDaejeon 35015Republic of Korea

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is a‘highly transmissible respiratory pathogen,leading to severe multiorgan ***,knowledge regarding SARS-CoV-2-induced cellular alterations is *** this study,we report that SARSCoV-2 aberrantly elevates mitochondrial bioenergetics and activates the EGFR-mediated cell survival signal cascade during the early stage of viral ***-CoV-2 causes an increase in mitochondrial transmembrane potential via the SARS-CoV-2 RNAnucleocapsid cluster,thereby abnormally promoting mitochondrial elongation and the OXPHOS process,followed by enhancing ATP ***,SARS-CoV-2 activates the EGFR signal cascade and subsequently induces mitochondrial EGFR trafficking,contributing to abnormal OXPHOS process and viral *** EGFR inhibitors remarkably reduce SARS-CoV-2 propagation,among which vandetanib exhibits the highest antiviral *** of SARS-CoV-2-infected cells with vandetanib decreases SARS-CoV-2-induced EGFR trafficking to the mitochondria and restores SARS-CoV-2-induced aberrant elevation in OXPHOS process and ATP generation,thereby resulting in the reduction of SARS-CoV-2 ***,oral administration of vandetanib to SARS-CoV-2-infected hACE2 transgenic mice reduces SARS-CoV-2 propagation in lung tissue and mitigates SARS-CoV-2-induced lung *** also exhibits potent antiviral activity against various SARS-CoV-2 variants of concern,including alpha,beta,delta and omicron,in in vitro cell culture *** together,our findings provide novel insight into SARS-CoV-2-induced alterations in mitochondrial dynamics and EGFR trafficking during the early stage of viral infection and their roles in robust SARS-CoV-2 propagation,suggesting that EGFR is an attractive host target for combating COVID-19.

关键词： alterations aberrant thereby

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All-in-one glycol chitosan nanoparticles for co-delivery of doxorubicin and anti-PD-L1 peptide in cancer immunotherapy

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Bioactive Materials 2023年第10期28卷 358-375页

作者： Sukyung Song Man Kyu Shim Suah Yang Jaewan Lee Wan Su Yun Hanhee Cho Yujeong Moon Jin Young Min Eun Hee Han Hong Yeol Yoon Kwangmeyung Kim College of Pharmacy Graduate School of Pharmaceutical SciencesEwha Womans UniversitySeoul03760Republic of Korea Medicinal Materials Research Center Biomedical Research DivisionKorea Institute of Science and Technology(KIST)Seoul02792Republic of Korea KU-KIST Graduate School of Converging Science and Technology Korea UniversitySeoul02841Republic of Korea Department of Bioengineering Korea UniversitySeoul02841Republic of Korea Research Center for Bioconvergence Analysis Korea Basic Science Institute(KBSI)Cheongju28119Republic of Korea Department of toxicology College of PharmacyChungnam National UniversityDaejeon34134Republic of Korea

Synergistic immunotherapy of immune checkpoint blockade (ICB) and immunogenic cell death (ICD) has shown remarkable therapeutic efficacy in various cancers. However, patients show low response rates and undesirable outcomes to these combination therapies owing to the recycling mechanism of programmed death-ligand 1 (PD-L1) and the systemic toxicity of ICD-inducing chemotherapeutic drugs. Herein, we propose all-in-one glycol chitosan nanoparticles (CNPs) that can deliver anti-PD-L1 peptide (PP) and doxorubicin (DOX) to targeted tumor tissues for a safe and more effective synergistic immunotherapy. The PP-CNPs, which are prepared by conjugating ᴅ-form PP (NYSKPTDRQYHF) to CNPs, form stable nanoparticles that promote multivalent binding with PD-L1 proteins on the targeted tumor cell surface, resulting in effective lysosomal PD-L1 degradation in contrast with anti-PD-L1 antibody, which induces recycling of endocytosed PD-L1. Consequently, PP-CNPs prevent subcellular PD-L1 recycling and eventually destruct immune escape mechanism in CT26 colon tumor-bearing mice. Moreover, the ICD inducer, DOX is loaded into PP-CNPs (DOX-PP-CNPs) for synergistic ICD and ICB therapy, inducing a large number of damage-associated molecular patterns (DAMPs) in targeted tumor tissues with minimal toxicity in normal tissues. When the DOX-PP-CNPs are intravenously injected into CT26 colon tumor-bearing mice, PP and DOX are efficiently delivered to the tumor tissues via nanoparticle-derived passive and active targeting, which eventually induce both lysosomal PD-L1 degradation and substantial ICD, resulting in a high rate of complete tumor regression (CR: 60%) by a strong antitumor immune response. Collectively, this study demonstrates the superior efficacy of synergistic immunotherapy using all-in-one nanoparticles to deliver PP and DOX to targeted tumor tissues.

关键词： Chitosan nanoparticle Synergistic immunotherapy Immune checkpoint blockade Multivalent binding Immunogenic cell death

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Behavioral changes of water flea Daphnia *** exposed to the three toxicants diazinon,copper,and cadmium

Behavioral changes of water flea Daphnia *** exposed to the ...

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第三世界生态高峰会

作者： Yoon Sung Jin Lee Sung Kyu Yoon Hong Gi Park Hahn Oh korea institute of toxicology 100 jangdong Yuseong-gu Daejeon 305-343 korea korea institute of toxicology 100 jangdong Yuseong-gu Daejeon 305-343 korea korea institute of toxicology 100 jangdong Yuseong-gu Daejeon 305-343 korea Bioneer corporation 49-3 Munpyeong-dong Daedeok-gu Daejeon 306-220 korea

Behavioral changes of 2 to 3 days old water flea Daphnia *** were observed using an aqualann system,Prototype-Ⅲ,was developed for monitoring system of a hazardous chemicals management in water *** toxicity of three chemicals diazinon,copper,and cadmium to *** was determined by 24-h flow *** the experiments,the daphnids were not ted and were kept in 16-h of light, 8-h of darkness and at constant temperature to avoid any extrinsic *** behavior response of test animal was analyzed by changes of fractal dimension value （FDV）,it were computationally calculated in detecting the movement patterns of test animals,before and after the chemical *** FDV of test animal was sharply decreased by exposing daphnids to concentrations of 0.04 mg/L diazinon,0.1 mg/L copper and 0.5 mg/L *** abnormal behavior of daphnids after toxicants exposure was observed within 1.6-h for diazinon,0.8-h for copper,and 1.5-h for cadmium, *** of 24-h LC values indicated that *** was lower sensitive to diazinon than the most water flea such as D. magna,Ceriodaphnia dubia,and Monia ***,the sensitivity of test animal to other toxicants higher than brine shrimp （Artemia salina） water flea （Ceriodaphnia dubia） for copper,and brine shrimp,rotifer （Brachionus calyciflorus,***）,and water flea （***） for *** response of the test animal exposed to toxicants can suggest that it was related to physiological stress influenced different chemical characteristics in each toxicant and the concentration of the ***,it suggests that monitoring system used in this study could be very useful tool for not only ecotoxicological assessment of various toxicants after exposure in the natural environment but also detection of sudden changes in concentrations of informed or not informed toxicants discharged in water body.

关键词： Behavioral changes of water flea Daphnia cf.similis exposed to the three toxicants diazinon,copper,and cadmium

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SYNCRIP controls miR-137 and striatal learning in animal models of methamphetamine abstinence

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Acta Pharmaceutica Sinica B 2022年第8期12卷 3281-3297页

作者： Baeksun Kim Sung Hyun Tag Eunjoo Nam Suji Ham Sujin Ahn Juhwan Kim Doo-Wan Cho Sangjoon Lee Young-Su Yang Seung Eun Lee Yong Sik Kim Il-Joo Cho Kwang Pyo Kim Su-Cheol Han Heh-In Im Convergence Research Center for Diagnosis Treatment and Care System of Dementia(DTC)Korea Institute of Science and Technology(KIST)Seoul 02792Republic of Korea Division of Bio-Medical Science&Technology KIST SchoolKorea University of Science and Technology(UST)Seoul 02792Republic of Korea Center for Neuroscience KISTSeoul 02792Republic of Korea Animal Model Research Center Jeonbuk Department of Inhalation ResearchKorea Institute of Toxicology(KIT)Korea Research Institute of Chemical Technology(KRICT)Jeongeup 56212Republic of Korea Research Animal Resource Center KISTSeoul 02792Republic of Korea Department of Pharmacology Seoul National University College of MedicineSeoul 03080Republic of Korea Center for BioMicrosystems KISTSeoul 02792Republic of Korea Department of Applied Chemistry Kyung Hee UniversityGyeonggi-do 17104Republic of Korea

Abstinence from prolonged psychostimulant use prompts stimulant withdrawal *** adaptations within the dorsal striatum have been considered the main hallmark of stimulant abstinence. Here we explored striatal miRNA-target interaction and its impact on circulating miRNA marker as well as behavioral dysfunctions in methamphetamine(MA) abstinence. We conducted miRNA sequencing and profiling in the nonhuman primate model of MA abstinence, followed by miRNA qPCR,LC-MS/MS proteomics, immunoassays, and behavior tests in mice. In nonhuman primates, MA abstinence triggered a lasting upregulation of miR-137 in the dorsal striatum but a simultaneous downregulation of circulating miR-137. In mice, aberrant increase in striatal miR-137-dependent inhibition of SYNCRIP essentially mediated the MA abstinence-induced reduction of circulating miR-137. Pathway modeling through experimental deduction illustrated that the MA abstinence-mediated downregulation of circulating miR-137 was caused by reduction of SYNCRIP-dependent miRNA sorting into the exosomes in the dorsal striatum. Furthermore, diminished SYNCRIP in the dorsal striatum was necessary for MA abstinence-induced behavioral bias towards egocentric spatial learning. Taken together, our data revealed circulating miR-137 as a potential blood-based marker that could reflect MA abstinence-dependent changes in striatal miR-137/SYNCRIP axis, and striatal SYNCRIP as a potential therapeutic target for striatum-associated cognitive dysfunction by MA withdrawal syndrome.

关键词： Methamphetamine Abstinence Withdrawal Striatum miR-137 SYNCRIP Biomarker Behavior

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Evaluation of spermatogenesis and fertility in F1 male rats after in utero and neonatal exposure to extremely low frequency electromagnetic fields

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Asian Journal of Andrology 2005年第2期7卷 189-194,页

作者： M.K.Chung S.J.Lee Y.B.Kim S.C.Park D.H.Shin S.H.Kim J.C.Kim Reproductive toxicology Division Korea Institute of ToxicologyKorea Research Institute of Chemical TechnologyDaejeon 305-600Korea College of Veterinary Medicine Chungbuk National UniversityCheongju 361-763Korea College of Veterinary Medicine Kyungpook National UniversityDaegu 702-701Korea College of Veterinary Medicine Chonnam National UniversityGwangju 500-757Korea

Aim:To determine whether in utero and neonatal exposure to a 60 Hz extremely low frequency electromagnetic field (EMF) results in spermatotoxicity and reproductive dysfunction in the F1 offspring of ***:Age-matched, pregnant Sprague-Dawley rats were exposed continuously (21 h/day) to a 60 Hz EMF at field strengths of 0 (sham control),5,83.3 or 500 μT from day 6 of gestation through to day 21 of *** experimentally generated magnetic field was monitored continuously (uninterrupted monitoring over the period of the study) throughout the ***:No exposure-related changes were found in exposed or sham-exposed animals with respect to the anogenital distance,preputial separation,testis weight,testicular histology,sperm count,daily sperm production, sperm motility,sperm morphology and reproductive capacity of F1 ***:Exposure of Sprague- Dawley rats to a 60 Hz EMF at field strengths of up to 500 μT from day 6 of gestation to day 21 of lactation did not produce any detectable alterations in offspring spermatogenesis and fertility.

关键词： spermatogenesis electromagnetic fields prenatal exposure postnatal exposure rat

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Evaluation of particle growth systems for sampling and analysis of atmospheric fine particles

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Particuology 2011年第6期9卷 606-610页

作者： Dae Seong Kim Sang Bum Hong Jung-Taek Kwon Kihong Park Department of Environmental Science and Engineering Gwangju Institute of Science and Technology korea Polar Research institute Laboratory of toxicology College of Veterinary Medicine Seoul National University

Three types of water-based condensational growth systems, which can enable particles to grow in size to facilitate sampling and subsequent chemical analysis, were evaluated. The first one is a mixing type growth system where aerosols are mixed with saturated water vapor, the second one is a thermal diffusive growth system where warm flow enters cold-walled tube, and the third one is a laminar flow type where cold flow enters a warm wet-wall tube. Hygroscopic sodium chloride （NaCl）, ammonium sulfate （（NH4）2SO4） and ammonium nitrate （NH4N03）, and non-hygroscopic polystyrene latex （PSL） particles, in the size range of 50-400 nm, were used to determine their growth factors through the growth systems. Our data showed that the third-type growth system could enable particles to grow most efficiently regardless of their hygroscopic property. Collection efficiency of particles in the size range of 0.05-2.5 μm, in a continuous aerosol sampler after they passed through the third-type growth system was about 100%, suggesting that the third-type growth system would he the most useful among the tested growth systems for sampling and subsequent chemical analysis of fine and ultrafine particles.

关键词： Particle growth chamber Condensational growth Particle sampler Hygroscopic particles

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Tilorone confers robust in vitro and in vivo antiviral effects against severe fever with thrombocytopenia syndrome virus

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Virologica Sinica 2022年第1期37卷 145-148页

作者： Jingjing Yang Yunzheng Yan Qingsong Dai Jiye Yin Lei Zhao Yuexiang Li Wei Li Wu Zhong Ruiyuan Cao Song Li School of Pharmaceutical Sciences Hainan UniversityHaikou570228China National Engineering Research Centre for the Emergency Drug Beijing Institute of Pharmacology and ToxicologyBeijing100850China

Dear Editor,Severe fever with thrombocytopenia syndrome virus(SFTSV),an emerging pathogen,is a tick-borne bunyavirus belonging to the genus Bandavirus in the family Phenuiviridae(Kuhn et al.,2020).This pathogen was first identified in China during the heightened surveillance of acute febrile illness in 2009,and has been reported to cause several outbreaks in eastern Asia areas,including China,Japan,and korea(Yu et al.,2011).

关键词： al. fever acute

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Targeted knockout of duox causes defects in zebrafish growth, thyroid development, and social interaction

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Journal of Genetics and Genomics 2019年第2期46卷 101-104页

作者： Jong-Su Park Tae-Ik Choi Oc-Hee Kim Ted Inpyo Hong Woo-Keun Kim Won-Jae Lee Cheol-Hee Kim Department of Biology Chungnam National University Biosystem Research Group Korea Institute of Toxicology School of Biological Sciences Seoul National University

Reactive oxygen species(ROS) are believed to be inevitable and toxic by-products produced during cellular respiration. However,several lines of evidence show that diverse extracellular signals can activate ROS product... 详细信息

关键词： KO In Targeted knockout of duox causes defects in zebrafish growth thyroid development and social interaction

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Nelumbo Nucifera leaf extract attenuated pancreatic β-cells toxicity induced by interleukin-1β and interferon-γ, and increased insulin secrection of pancreatic β-cells in streptozotocin-induced diabetic rats

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Journal of Traditional Chinese Medicine 2016年第1期36卷 71-77页

作者： Bhesh Raj Sharma Min Suk Kim Dong Young Rhyu Department of Oriental Medicine Resources and institute of korean Medicine Industry Mokpo National UniversityJeonnam 534-729Republic of Korea Department of Environmental and Molecular toxicology Oregon State UniversityCorvallisOR 97331The United States of America

OBJECTIVE: To evaluate the effect of Nelumbo Nucifera leaf water extract(NNLE) on insulinoma(RIN)cells induced by interleukin-1β(IL-1β) and interferon-g(IFN-γ), and injured pancreatic β-cells induced by Streptozotocin(STZ) in ***: The anti-oxidative effects of NNLE were assessedusing 1,1-diphenyl-2-picrylhydrazyl(DPPH)and nitric oxide(NO) scavenging assays. The inhibitory effect of NNLE on α-glucosidase and DPP(dipeptidyl peptidase)-IV was measured in vitro. Pancreatic β-cell protective and insulin secretory effects were assessed, using IL-1β and IFN-γ-induced rat RIN cells. STZ-induced diabetic rats were treated with 50, 100, and 400 mg/kg NNLE for 4 weeks. The effects of NNLE on blood glucose(BG), body weight(BW), and lipid profiles were ***: NNLE inhibited DPPH, NO, α-glucosidase,and DPP-Ⅳ which were directly linked to the function of β-cells. Furthermore, NNLE protected RIN cells from toxicity induced by IL-1β and IFN-γ, decreased NO production, and increased insulin secretion. NNLE caused a significant reduction in blood glucose, triglyceride(TG), total cholesterol(TC),blood urea nitrogen(BUN), and creatinine in STZ-induced diabetic rats. Furthermore, it significantly decreased BW loss in STZ-induced diabetic ***: Our results suggest that NNLE reduced the toxicity in insulinoma cells and increased insulin secretion in pancreatic β-cells in STZ-induced diabetic rats.

关键词：中医理论预防养生

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Toxicity and Carcinogenicity of Ozone in Combination with 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone and Dibutyl Phthalate in B6C3F1 Mice for 16 and 32 Weeks

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Biomedical and Environmental Sciences 2009年第3期22卷 216-222页

作者： MIN YOUNG KIM M YUNG CHO Laboratory of toxicology College of Veterinary MedicineSeoul National University Biological Engineering Department Massachusetts Institute of Technology

Objective To evaluate the toxic and carcinogenic potential of ozone alone or in combination with 4-（N-methyl-N-nitrosamino）-1-（3-pyridyl）-1-butanone （NNK） and/or dibutyl phthalate （DBP）. Methods Male and female B6C3F1 mice were exposed, through inhalation, intravenous administration and diet, to 0.5 ppm of ozone, 1.0 mg/kg of NNK and 5000 ppm of DBP, individually and in combination for 16 and 32 weeks. Results No treatment-related death was seen, but significant differences in body and organ weights between control and treated mice were observed during the study. No incidence of lung tumor incidence was recorded in mice exposed to either ozone alone or combined treatment. Oviductal carcinomas were observed in female mice exposed to ozone or DBP alone for 16 weeks and ozone in combination with NNK and DBP for 32 weeks. Conclusion Although ozone alone and in conjunction with NNK and/or DBP does not induce lung cancer under our experimental conditions, they induce oviductal carcinomas in B6C3F1 mice.

关键词： Ozone NNK DBP Combined treatment Toxicity Carcinogenicity

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