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Drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions

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Virologica Sinica 2024年第1期39卷 123-133页

作者： Hongbo Guo Dan Liu Kuan Liu Yao Hou Chunyang Li Qiudi Li Xiaohui Ding Monique M.A.Verstegen Jikai Zhang Lingli Wang Yibo Ding Renxian Tang Xiucheng Pan Kuiyang Zheng Luc J.Wvan der Laan Qiuwei Pan Wenshi Wang department of pathogen biology and immunology Jiangsu Key Laboratory of Immunity and MetabolismJiangsu International Laboratory of Immunity and MetabolismXuzhou Medical UniversityXuzhou221004China department of Gastroenterology and Hepatology Erasmus MC-University Medical CenterRotterdamNL-3015 CNthe Netherlands department of Surgery Erasmus MC Transplant InstituteUniversity Medical CenterRotterdam3015CENL-3015 CNthe Netherlands department of Infectious Diseases The Affiliated Hospital of Xuzhou Medical UniversityXuzhou221002China

Hepatitis E virus(HEV)infection can cause severe complications and high mortality,particularly in pregnant women,organ transplant recipients,individuals with pre-existing liver disease and immunosuppressed ***,there are still unmet needs for treating chronic HEV ***,we screened a best-in-class drug repurposing library consisting of 262 drugs/*** screening,we identified vidofludimus calcium and pyrazofurin as novel anti-HEV *** calcium is the next-generation dihydroorotate dehydrogenase(DHODH)inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 *** selectively targets uridine monophosphate synthetase(UMPS).Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV ***,both drugs exhibited a sizeable therapeutic window against *** instance,the IC50 value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in ***,their anti-HEV mode of action depends on the blockage of pyrimidine ***,two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants(Y1320H,G1634R).Their combination with IFN-αresulted in synergistic antiviral *** conclusion,we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV *** on their antiviral potency,and also the favorable safety profile identified in clinical studies,our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.

关键词： Hepatitis Evirus(HEV) Drug repurposing Vidofludimus calcium Pyrazofurin Pyrimidine biosynthesis

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Identification of gene classifier and modules associated with SARS-CoV-2 ARI in nasal swab

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Genes & Diseases 2024年第1期11卷 38-41页

作者： Pandikannan Krishnamoorthy Athira S.Raj Himanshu Kumar department of Biological Sciences Laboratory of Immunology and Infectious Disease BiologyIndian Institute of Science Education and Research(llSER)BhopalBhopalMP 462066India Laboratory of Host Defense WPl ImmunologyFrontier ResearchCentreOsakaUniversityOsaka 5650871Japan

During a sudden viral pandemic,where the pathogenesis and nature of the infection are unclear,early and accurate identification of the patients infected with the pandemiccausing pathogen is crucial to prevent excess *** the coronavirus disease 2019(COvID-19)pandemic,early diagnosis of severe acute respiratory syndrome virus-2(SARS-CoV-2)is limited by the incidence of the symptoms that are shared with acute respiratory illnesses(ARl)caused by other pathogens.

关键词： acute diagnosis respiratory

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Gut microbiota dysbiosis contributes toα-synuclein-related pathology associated with C/EBPβ/AEP signaling activation in a mouse model of Parkinson’s disease

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Neural Regeneration Research 2024年第9期19卷 2081-2088页

作者： Xiaoli Fang Sha Liu Bilal Muhammad Mingxuan Zheng Xing Ge Yan Xu Shu Kan Yang Zhang Yinghua Yu Kuiyang Zheng Deqin Geng Chun-Feng Liu department of Neurology and Clinical Research Center of Neurological Disease The Second Affiliated Hospital of Soochow UniversitySuzhouJiangsu ProvinceChina department of Neurology Affiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsu ProvinceChina Jiangsu Key Laboratory of Immunity and Metabolism Department of Pathogen Biology and ImmunologyXuzhou Medical UniversityXuzhouJiangsu ProvinceChina department of Neurology Xuzhou Central HospitalXuzhouJiangsu ProvinceChina Jiangsu Key Laboratory of Neuropsychiatric Disease and Institute of Neuroscience Soochow UniversitySuzhouJiangsu ProvinceChina

Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal *** dysfunction can precede the onset of motor symptoms by several *** microbiota dysbiosis is involved in the pathogenesis of Parkinson’s disease,whether it plays a causal role in motor dysfunction,and the mechanism underlying this potential effect,remain ***/enhancer binding proteinβ/asparagine endopeptidase(C/EBPβ/AEP)signaling,activated by bacterial endotoxin,can promoteα-synuclein transcription,thereby contributing to Parkinson’s disease *** this study,we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling,α-synuclein-related pathology,and motor symptoms using a rotenone-induced mouse model of Parkinson’s disease combined with antibiotic-induced microbiome depletion and fecal microbiota *** found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier,as well as activation of the C/EBP/AEP pathway,α-synuclein aggregation,and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor ***,treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with ***,we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits,intestinal inflammation,and *** of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits,intestinal inflammation,endotoxemia,and intestinal barrier *** results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits,C/EBPβ/AEP signaling activation,andα-synuclein-related pathology in a rotenone-induced mouse model of Parkinson’s ***,our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that c

关键词： C/EBP/AEP signaling pathway endotoxemia fecal microbiota transplantation intestinal barrier intestinal inflammation microbiota-gut-brain axis Parkinson’s disease

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Research progress toward the influence of mosquito salivary proteins on the transmission of mosquito-borne viruses

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Insect Science 2024年第3期31卷 663-673页

作者： Zhao-Yang Wang Kai-Xiao Nie Ji-Chen Niu Gong Cheng Tsinghua University-Peking University Joint Center for Life Sciences School of MedicineTsinghua UniversityBejingChina Institute of Infectious Diseases Shenzhen Bay LaboratoryShenzhenGuangdongChina department of pathogen biology School of Basic MedicineShandong First Medical University&Shandong Academy of Medical SciencesJinanChina

Mosquito-borne viruses(MBVs)are a large class of viruses transmitted mainly through mosquito bites,including dengue virus,Zika virus,Japanese encephalitis virus,West Nile virus,and chikungunya virus,which pose a major threat to the health of people around the *** global warming and extended human activities,the incidence of many MBVs has increased *** saliva contains a variety of bioactive protein *** not only enable blood feeding but also play a crucial role in regulating local infection at the bite site and the remote dissemination of MBVs as well as in remodeling the innate and adaptive immune responses of host ***,we review the physiological functions of mosquito salivary proteins(MSPs)in detail,the influence and the underlying mechanism of MSPs on the transmission of MBVs,and the current progress and issues that urgently need to be addressed in the research and development of MSP-based MBV transmission blocking vaccines.

关键词： immune response mosquito-borne virus mosquito salivary protein saliva vaccine transmission

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Vaccinia virus viability under different environmental conditions and different disinfectants treatment

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Biosafety and Health 2024年第1期6卷 21-27页

作者： Shan Mei Liang Wei Yu Xie Fei Zhao Yu Huang Zhangling Fan Yamei Hu Liming Wang Lingwa Wang Ying Wang Fengwen Xu Fei Guo NHC Key Laboratory of Systems biology of pathogens National Institute of Pathogen Biology and Center for AIDS ResearchChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China department of Otolaryngology Head and Neck Surgery Beijing Tongren HospitalCapital Medical UniversityBejing 100730China Clinical Laboratory Emergency General HospitalBeijing 100028China

Monkeypox(mpox)outbreak in 2022 has caused more than 91,000 cases,has spread to 115 countries,regions,and territories,and has thus attracted much *** stability of poxvirus particles in the environment is recognized as an important factor in determining their ***,few studies have investigated the persistence of poxviruses on material surfaces under various environmental conditions,and their sensitivity to ***,we systematically measured the stability of vaccinia virus(VACV)under different environmental conditions and sensitivity to inactivation methods via plaque assay,quantitative real‐time polymerase chain reaction(qPCR),and Gaussia luciferase(G‐luciferase)reporter *** results show that VACV is stable on the surface of stainless steel,glass,clothing,plastic,towel,A4 paper,and tissue and persists much longer at 4℃ and?20℃,but is effectively inactivated by ultraviolet(UV)irradiation,heat treatment,and chemical *** study raises the awareness of long persistence of poxviruses in the environment and provides a simple solution to inactivate poxviruses using common disinfectants,which is expected to help the control and prevention of mpox virus and future poxvirus outbreaks.

关键词： Poxvirus Mpox virus Vaccinia virus Persistence Disinfectant

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SARS-CoV-2 breakthrough infections following inactivated vaccine vaccination induce few neutralizing antibodies against the currently emerging Omicron XBB variants

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Virologica Sinica 2024年第1期39卷 173-176页

作者： Fan Shen Chun Liang Cui-Xian Yang Ying Lu An-Qi Li Ying Duan Mi Zhang c Ren-Rong Tian a Xing-Qi Dong Yong-Tang Zheng Wei Pang Key Laboratory of Bioactive Peptides of Yunnan Province/Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences KIZ-CUHK Joint Laboratory of Bioresources and Molecular Research in Common DiseasesKunming Institute of ZoologyChinese Academy of SciencesKunming650223China University of Chinese Academy of Sciences Beijing100049China Yunnan Provincial Infectious Disease Hospital Kunming650399China department of pathogen biology and immunology Faculty of Basic Medical ScienceKunming Medical UniversityKunming650500China

Dear Editor,COVID-19 inactivated vaccines have been extensively administered ***,the majority of the Chinese population has experiencedbreakthrough infections from SARS-CoV-2 ancestral,Delta or Omicronvariants over the past three years,particularly during the wave of Omicron BA.5 and BA.7 variants at the end of 2022(Zhu et al.,2023).Subsequently,new Omicron variants,such as BQ.1,BQ.1.1,XBB,XBB.1/XBB.1.9,and XBB.1.5/XBB.1.9.1,are emerging in China(Yueetal.,2023;Zhu et al.,2023).Therefore,it is an urgentneed and a publichealth imperative to assess the extent of the immunoprotection established in this population.

关键词： breakthrough neutral Omi

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Eosinophils promote CD8+ T cell memory generation to potentiate anti-bacterial immunity

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1230-1243页

作者： Jun Zhou Jiaqi Liu Bingjing Wang Nan Li Juan Liu Yanmei Han Xuetao Cao Institute of immunology Zhejiang University School of MedicineHangzhou 310058China National Key Laboratory of Immunity and Inflammation Institute of ImmunologyNaval Medical UniversityShanghai 200433China department of immunology Center for ImmunotherapyInstitute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical SciencesBeijing 100005China Institute of immunology College of Life SciencesNankai UniversityTianjin 300071China

Memory CD8+T cell generation is crucial for pathogen elimination and effective vaccination against *** cellular and molecular circuitry that underlies the generation of memory CD8+T cells remains *** can modulate inflammatory allergic responses and interact with lymphocytes to regulate their functions in immune *** we report that eosinophils are required for the generation of memory CD8+T cells by inhibiting CD8+T cell ***-deficient mice display significantly impaired memory CD8+T cell response and weakened resistance against Listeria monocytogenes(L.m.)***,eosinophils secrete interleukin-4(IL-4)to inhibit JNK/Caspase-3 dependent apoptosis of CD8+T cells upon *** in ***,active eosinophils are recruited into the spleen and secrete more IL-4 to suppress CD8+T cell apoptosis during early stage of *** in *** transfer of wild-type(WT)eosinophils but not IL-4-deficient eosinophils into eosinophil-deficient mice could rescue the impaired CD8+T cell memory ***,our findings suggest that eosinophil-derived IL-4 promotes the generation of CD8+T cell memory and enhances immune defense against *** study reveals a new adjuvant role of eosinophils in memory T cell generation and provides clues for enhancing the vaccine potency via targeting eosinophils and related cytokines.

关键词： impaired immunity spleen

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SARS-CoV-2 and innate immunity:the good,the bad,and the"goldilocks"

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Cellular & Molecular immunology 2024年第2期21卷 171-183页

作者： Benjamin L.Sievers Mark T.K.Cheng Kata Csiba Bo Meng Ravindra K.Gupta department of Medicine University of CambridgeCambridgeUK Cambridge Institute of Therapeutic immunology&Infectious Disease(CITID) Department of MedicineUniversity of CambridgeCambridgeUk

An ancient conflict between hosts and pathogens has driven the innate and adaptive arms of *** about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that can be leveraged *** humoral response to SARS-CoV-2 infection has been the focus of intense research,and the role of the innate immune system has received significantly less ***,we review current knowledge of the innate immune response to SARS-CoV-2 infection and the various means SARS-CoV-2 employs to evade innate defense *** also consider the role of innate immunity in SARS-CoV-2 vaccines and in the phenomenon of long COVID.

关键词： SARS-CoV-2 Innate immune response Interferon Cytokines Inflammation Antiviral targets

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Lecithin-cholesterol acyltransferase is a potential tumor suppressor and predictive marker for hepatocellular carcinoma metastasis

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World Journal of Gastrointestinal Oncology 2024年第8期16卷 3651-3671页

作者： Yan Li Li-Na Jiang Bo-Kang Zhao Mei-Ling Li Yi-Yun Jiang Yi-Si Liu Shu-Hong Liu Li Zhu Xin Ye Jing-Min Zhao department of Pathology and Hepatology The Fifth Medical Center of Chinese PLA General HospitalBeijing 100039China department of Hepatology Center of Infectious Diseases and Pathogen BiologyThe First Hospital of Jilin UniversityChangchun 130061Jilin ProvinceChina First department of Liver Disease Center Beijing Youan HospitalCapital Medical UniversityBeijing 100069China Key Laboratory of pathogenic Microbiology and immunology Institute of MicrobiologyChinese Academy of SciencesBeijing 100101China Savaid Medical School University of Chinese Academy of SciencesBeijing 100190China department of Pathology The Fifth Medical Center of Chinese PLA General HospitalBeijing 100039China

BACKGROUND Hepatocellular carcinoma(HCC)is a major cause of cancer mortality worldwide,and metastasis is the main cause of early recurrence and poor ***,the mechanism of metastasis remains poorly *** To determine the possible mechanism affecting HCC metastasis and provide a possible theoretical basis for HCC *** The candidate molecule lecithin-cholesterol acyltransferase(LCAT)was screened by gene microarray and bioinformatics *** expression levels of LCAT in clinical cohort samples was detected by quantitative realtime polymerase chain reaction and western *** proliferation,migration,invasion and tumor-forming ability were measured by Cell Counting Kit-8,Transwell cell migration,invasion,and clonal formation assays,*** formation was detected in nude mice after LCAT gene knockdown or *** immunohistochemistry for Ki67,E-cadherin,N-cadherin,matrix metalloproteinase 9 and vascular endothelial growth factor were performed in liver tissues to assess the effect of LCAT on *** set enrichment analysis(GSEA)on various gene signatures were analyzed with GSEA version *** machine-learning algorithms(random forest,support vector machine,and logistic regression)were applied to predict HCC metastasis in The Cancer Genome Atlas and GEO *** LCAT was identified as a novel gene relating to HCC metastasis by using gene microarray in HCC *** was significantly downregulated in HCC tissues,which is correlated with recurrence,metastasis and poor outcome of HCC *** analysis indicated that LCAT inhibited HCC cell proliferation,migration and invasion both in vitro and in *** data showed that LCAT was negatively associated with HCC size and metastasis(HCC size≤3 cm vs 3-9 cm,P9 cm,P<0.01;metastatic-free HCC vs extrahepatic metastatic HCC,P<0.05).LCAT suppressed the growth,migration and invasion of HCC cell lines via PI3K/A

关键词： Lecithin-cholesterol acyltransferase Tumor suppressor gene Hepatocellular carcinoma PI3K/AKT/mTOR Predicting model

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Hepatic Zbtb18 (Zinc Finger and BTB Domain Containing 18) alleviates hepatic steatohepatitis via FXR (Farnesoid X Receptor)

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Signal Transduction and Targeted Therapy 2024年第2期9卷 766-781页

作者： Lei Zhang Jiabing Chen Xiaoying Yang Chuangpeng Shen Jiawen Huang Dong Zhang Naihua Liu Chaonan Liu Yadi Zhong Yingjian Chen Kaijia Tang Jingyi Guo Tianqi Cui Siwei Duan Jiayu Li Shangyi Huang Huafeng Pan Huabing Zhang Xiaoqiang Tang Yongsheng Chang Yong Gao State Key Laboratory of Traditional Chinese Medicine Syndrome Science and Technology Innovation CenterGuangzhou University of Chinese MedicineGuangzhouChina Key Laboratory of Immune Microenvironment and Disease(Ministry of Education) Tianjin Key Laboratory of Cellular Homeostasis and DiseaseDepartment of Physiology and PathophysiologyTianjin Medical UniversityTianjinChina Jiangsu Key Laboratory of Immunity and Metabolism Department of Pathogen Biology and ImmunologyJiangsu International Laboratory of Immunity and MetabolismXuzhou Medical UniversityXuzhouChina department of Endocrinology The First Clinical CollegeGuangzhou University of Chinese MedicineGuangdongChina The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine ShenzhenChina Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine in Prevention and Treatment of Tumor Nanjing University of Chinese MedicineNanjingChina department of Biochemistry and Molecular biology Metabolic Disease Research CenterSchool of Basic MedicineAnhui Medical UniversityHefeiChina Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE State Key Laboratory of BiotherapyWest China Second University HospitalSichuan UniversityChengduChina

A lasting imbalance between fatty acid synthesis and consumption leads to non-alcoholic fatty liver disease(NAFLD),coupled with hepatitis and insulin *** the details of the underlying mechanisms are not fully ***,we unraveled that the expression of the transcription factor Zbtb18 is markedly decreased in the livers of both patients and murine models of *** Zbtb18 knockout promoted NAFLD features like impaired energy expenditure and fatty acid oxidation(FAO),and induced insulin ***,hepatic Zbtb18 overexpression alleviated hepato-steatosis,insulin resistance,and hyperglycemia in mice fed on a high-fat diet(HFD)or in diabetic ***,in vitro and in vivo mechanistic studies revealed that Zbtb18 transcriptional activation of Farnesoid X receptor(FXR)mediated FAO and Clathrin Heavy Chain(CLTC)protein hinders NLRP3 inflammasome *** key mechanism by which hepatocyte’s Zbtb18 expression alleviates NAFLD and consequent liver fibrosis was further verified by FXR’s deletion and forced expression in mice and cultured mouse primary hepatocytes(MPHs).Moreover,CLTC deletion significantly abrogated the hepatic Zbtb18 overexpression-driven inhibition of NLRP3 inflammasome activity in ***,Zbtb18 transcriptionally activates the FXR-mediated FAO and CLTC expression,which inhibits NLRP3 inflammasome’s activity alleviating inflammatory stress and insulin resistance,representing an attractive remedy for hepatic steatosis and fibrosis.

关键词： hepatic Hepatic impaired

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