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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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The role of m^(6)A RNA methylation in autoimmune diseases: Novel therapeutic opportunities

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Genes & diseases 2024年第1期11卷 252-267页

作者： Yunan Shan Wei Chen Yanbin Li The First Clinical Medical College Shandong University of Traditional Chinese MedicineJinanShandong 250013China Department of Neurology The First Affiliated Hospital of Shandong First Medical University&Shandong Provincial Qjanfoshan HospitalShandong Institute of NeuroimmunologyShandong Key Laboratory of Rheumatic Disease and Translational MedicineJinanShandong 250013China Department of Gastroenterology Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200233China

N6-methyladenosine m^(6)A modifications,as one of the most common forms of in-ternal RNA chemical modifications in eukaryotic cells,have gained increasing attention in recent *** m^(6)A RNA modifications exert various crucial roles in various biological pro-cesses,such as embryonic development,neurogenesis,circadian rhythms,and *** advances have highlighted that m^(6)A RNA modification plays an important role in im-mune response,especially in the initiation and progression of autoimmune *** this re-view,we summarized the regulatory mechanisms of m^(6)A methylation and its biological functions in the immune system and mainly focused on recent progress in research on the po-tential role of m^(6)A RNA methylation in the pathogenesis of autoimmune diseases,thus providing possible biomarkers and potential targets for the prevention and treatment of auto-immunediseases.

关键词： Adaptive immunity autoimmune diseases Innate immunity Immune response m^(6)A RNA methylation

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Unraveling brain aging through the lens of oral microbiota

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Neural Regeneration Research 2025年第7期20卷 1930-1943页

作者： Qinchao Hu Si Wang Weiqi Zhang Jing Qu Guang-Hui Liu State key laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijingChina Hospital of Stomatology Guanghua School of StomatologyGuangdong Provincial Key Laboratory of StomatologySun Yat-sen UniversityGuangzhouGuangdong ProvinceChina Advanced Innovation Center for Human Brain Protection and National Clinical Research Center for Geriatric Disorders Xuanwu HospitalCapital Medical UniversityBeijingChina Aging Translational medicine Center International Center for Aging and CancerBeijing Municipal Geriatric Medical Research CenterXuanwu HospitalCapital Medical UniversityBeijingChina CAS key laboratory of Genomic and precision medicine Beijing Institute of GenomicsChinese Academy of Sciences and China National Center for BioinformationBeijingChina University of Chinese Academy of Sciences BeijingChina Institute for Stem Cell and Regeneration Chinese Academy of SciencesBeijingChina Aging Biomarker Consortium BeijingChina State key laboratory of Stem Cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijingChina Beijing Institute for Stem Cell and Regenerative medicine BeijingChina

The oral cavity is a complex physiological community encompassing a wide range of *** of oral microbiota can lead to various oral infectious diseases,such as periodontitis and tooth decay,and even affect systemic health,including brain aging and neurodegenerative *** studies have highlighted how oral microbes might be involved in brain aging and neurodegeneration,indicating potential avenues for intervention *** this review,we summarize clinical evidence demonstrating a link between oral microbes/oral infectious diseases and brain aging/neurodegenerative diseases,and dissect potential mechanisms by which oral microbes contribute to brain aging and *** also highlight advances in therapeutic development grounded in the realm of oral microbes,with the goal of advancing brain health and promoting healthy aging.

关键词： Alzheimer's disease brain aging multiple sclerosis neurodegeneration neurodegenerative diseases oral microbiota Parkinson's disease periodontitis bacteria Porphyromonas gingivalis

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Identification of key Blood Biomarkers Linking Di(2-ethylhexyl)Phthalate and autoimmune diseases in Adolescents Mice

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Biomedical and Environmental Sciences 2024年第5期37卷 521-525页

作者： XU Xiao Mei LI Xiao Lu HU Die CAI Xiao Yue LI Qi Meng ZHENG Yuan Zhuo CAI Yang QI Yin Yin XU Tao ZHAO Ling Li NING Xia Department of Infectious diseases Anhui Provincial Children’s HospitalHefei 231000AnhuiChina Department of Toxicology School of Public HealthKey Laboratory of Environmental Toxicology of Anhui Higher Education InstitutesAnhui Medical UniversityHefei 231000AnhuiChina School of Biology Food and EnvironmentHefei UniversityHefei 230601AnhuiChina

Di(2-ethylhexyl)phthalate(DEHP)is a widely used plasticizer known for its reproductive developmental and immune system toxicity,mainly through esophagal,dermal,and respiratory exposure^([1-3]).Maternal exposure to DEHP during pregnancy can lead to adverse birth outcomes in offspring,including impacts on the thyroid system of adolescent offspring^([2-4]).

关键词： Blood respiratory pregnancy

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基因组结构变异研究的前瞻性及临床应用

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Science Bulletin 2024年第6期69卷 705-708页

作者：陈仲中 Richard H.Finnell 雷云平王红艳 Obstetrics and Gynecology Hospital State Key Laboratory of Genetic EngineeringInstitute of Reproduction and DevelopmentFudan UniversityShanghai 200011China Shanghai Children’s Hospital School of MedicineShanghai Jiao Tong UniversityShanghai 200062China Center for precision Environmental Health Department of Molecular and Cellular BiologyBaylor College of MedicineHouston 77030USA Departments of Molecular and Human Genetics and medicine Baylor College of MedicineOne Baylor PlazaHouston 77030USA Shanghai key laboratory of Metabolic Remodelling and Health Institute of Metabolism and Integrative BiologyFudan UniversityShanghai 200438China Children’s Hospital of Fudan University Shanghai 201102China

The challenges and breakthroughs in human genetics can largely depend on the depth of exploring the missing heritability[1]and understanding of genetic variants,which enabled scientists to better elucidate the underlying causes of diseases and apply this knowledge in clinical *** genomes differ from one individual to another in the form of single nucleotide variants(SNVs),small insertions and deletions(indels)(<50 base pairs(bp)),and structural variants(SVs)[2].

关键词： diseases breakthrough insertion

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表位结构指导免疫优势转移的HPV交叉疫苗的理性设计

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Science Bulletin 2024年第4期69卷 512-525页

作者：王致萍王大宁陈洁高飞江雅楠杨澄宇钱兹英池鑫张姝玥许钰洁卢一涵沈璟佳张承宗李瑾瑾周立志李婷婷郑清炳俞海李少伟夏宁邵顾颖 State key laboratory of Vaccines for Infectious diseases Xiang An Biomedicine LaboratorySchool of Life SciencesSchool of Public HealthXiamen UniversityXiamen 361102China National Institute of Diagnostics and Vaccine Development in Infectious diseases State Key Laboratory of Molecular Vaccinology and Molecular DiagnosticsCollaborative Innovation Center of Biologic ProductsNational Innovation Platform for Industry-Education Integration in Vaccine ResearchXiamen UniversityXiamen 361102China Research Unit of Frontier Technology of Structural Vaccinology Chinese Academy of Medical SciencesXiamen 361102China Xiamen Innovax Biotech Co. Ltd.Xiamen 361022China

In vaccine development,broadly or cross-type neutralizing antibodies(bnAbs or cnAbs)are frequently targeted to enhance *** immunodominant antibodies could help fine-tune vaccine immunogenicity and augment the precision of immunization ***,the methodologies to capitalize on the attributes of bnAbs in vaccine design have not been clearly *** this study,we discovered a cross-type neutralizing monoclonal antibody,13H5,against human papillomavirus 6(HPV6)and *** nAb exhibited a marked preference for HPV6,demonstrating superior binding activity to virus-like particles(VLPs)and significantly higher prevalence in anti-HPV6 human serum as compared to HPV11 antiserum(90%vs.31%).Through co-crystal structural analysis of the HPV6 L1 pentamer:13H5 complex,we delineated the epitope as spanning four segments of amino acids(Phe42-Ala47,Gly172-Asp173,Glu255-Val275,and Val337-Tyr351)on the L1 surface *** interaction analysis and site-directed mutagenesis revealed that the Ser341 residue in the HPV6 HI loop plays a critical role in the interaction between 13H5 and *** Ser341 with alanine,which is the residue type present in HPV11 L1,almost completely abolished binding activity to *** swapping amino acids in the HPV11 HI loop with corresponding residues in HPV6 L1(Ser341,Thr338,and Thr339),we engineered chimeric HPV11-6HI ***,the chimeric HPV11-6HI VLPs shifted the high immunodominance of 13H5 from HPV6 to the engineered VLPs and yielded comparable neutralization titers for both HPV6 and HPV11 in mice and non-human *** approach paves the way for the design of broadly protective vaccines from antibodies within the main immunization reservoir.

关键词： Human papillomavirus Cross-neutralization antibody Immunodominance shift Vaccine design

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Plasma microRNA-15a/16-1-based machine learning for early detection of hepatitis B virus-related hepatocellular carcinoma

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肝脏研究（英文） 2024年第2期8卷 105-117页

作者： Huan Wei Songhao Luo Yanhua Bi Chunhong Liao Yifan Lian Jiajun Zhang Yuehua Huang Guangdong Provincial key laboratory of Liver Disease Research The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina School of Mathematics Sun Yat-sen UniversityGuangzhouChina Guangdong Provincial key laboratory of Liver Disease Research The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina School of Public Health Sun Yat-sen UniversityGuangzhouChina School of Mathematics Sun Yat-sen UniversityGuangzhouChina Guangdong Province key laboratory of Computational Science Sun Yat-sen UniversityGuangzhouChina Guangdong Provincial key laboratory of Liver Disease Research The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina Department of Infectious diseases The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina

Background and aims:Hepatocellular carcinoma(HCC),which is prevalent worldwide and has a high mortality rate,needs to be effectively *** aimed to evaluate the significance of plasma microRNA-15a/16-1(miR-15a/16)as a biomarker of hepatitis B virus-related HCC(HBV-HCC)using the machine learning *** study was the first large-scale investigation of these two miRNAs in HCC plasma samples.Methods:Using quantitative polymerase chain reaction,we measured the plasma miR-15a/16 levels in a total of 766 participants,including 74 healthy controls,335 with chronic hepatitis B(CHB),47 with compensated liver cirrhosis,and 310 with *** diagnostic performance of miR-15a/16 was examined using a machine learning model and compared with that of alpha-fetoprotein(AFP).Lastly,to validate the diagnostic efficiency of miR-15a/16,we performed pseudotemporal sorting of the samples to simulate progression from CHB to HCC.Results:Plasma miR-15a/16 was significantly decreased in HCC than in all control groups(P＜0.05 for all).In the training cohort,the area under the receiver operating characteristic curve(AUC),sensitivity,and average precision(AP)for the detection of HCC were higher for miR-15a(AUC=0.80,67.3％,AP=0.80)and miR-16(AUC=0.83,79.0％,AP=0.83)than for AFP(AUC=0.74,61.7％,AP=0.72).Combining miR-15a/16 with AFP increased the AUC to 0.86(sensitivity 85.9％)and the AP to 0.85 and was significantly superior to the other markers in this study(P＜0.05 for all),as further demonstrated by the detection error tradeoff ***,miR-15a/16 impressively showed potent diagnostic power in early-stage,small-tumor,and AFP-negative HCC.A validation cohort confirmed these ***,the simulated follow-up of patients further validated the diagnostic efficiency of miR-15a/16.Conclusions:We developed and validated a plasma miR-15a/16-based machine learning model,which exhibited better diagnostic performance for the early diagnosis of HCC compared to that of AFP.

关键词： Hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) microRNA-15a microRNA-16-1 Biomarker Machine learning Pseudotemporal ordering

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An intelligent DNA nanodevice for precision thrombus therapy

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Science China Chemistry 2024年第10期67卷 3195-3197页

作者： Yihao Zhou Qiangbin Wang CAS key laboratory of Nano-Bio Interface Division of Nanobiomedicine and i-LabSuzhou Instiute of Nano-Tech and Nano-BionicsChinese Academy of SciencesSuzhou 215123China

Obstruction of blood vessels(thrombosis)due to blood clots is one of the main causes of death worldwide and is associated with many cardiovascular diseases,such as myocardial infarction,ischemic stroke,and pulmonary embolism[1].Thrombolytic therapy is currently the preferred treatment for acute thrombosis and is administered intravenously with thrombolytic drugs,such as tissue plasminogen activator(tPA)[2].

关键词： drugs cardiovascular acute

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Total glucosides of paeony alleviates cGAS-STING-mediated diseases by blocking the STING-IRF3 interaction

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Chinese Journal of Natural medicines 2024年第5期22卷 402-415页

作者： XIU Ye WANG Sihao ZHANG Ping LI Chengwei WU Zhixin WEN Jincai XU Yingjie LV Guiji ZHAO Xiaomei DONG Xu CHEN Yichong LI Junjie WANG Yan ZOU Liang XIAO Xiaohe BAI Zhaofang School of Pharmacy Fujian University of Traditional Chinese MedicineFuzhou 350122China Department of Hepatology The Fifth Medical Center of PLA General HospitalBeijing 100039China China Military Institute of Chinese Materia Fifth Medical Center of Chinese PLA General HospitalBeijing 100039China Department of Pharmacy Medical Supplies Center of PLA General HospitalBeijing 100039China School of Food and Biological Engineering Chengdu UniversityChengdu 610106China National key laboratory of Kidney diseases Chinese PLA General HospitalBeijing 100039China

In the realm of autoimmune and inflammatory diseases,the cyclic GMP-AMP synthase(cGAS)stimulator of interferon genes(STING)signaling pathway has been thoroughly investigated and *** this,the clinical approval of drugs targeting the cGAS-STING pathway has been *** Total glucosides of paeony(TGP)is highly anti-inflammatory and is commonly used in the treatment of rheumatoid arthritis(RA),emerged as a subject of our *** found that the TGP markedly reduced the activation of the cGAS-STING signaling pathway,triggered by various cGAS-STING agonists,in mouse bone marrow-derived macrophages(BMDMs)and Tohoku Hospital Pediatrics-1(THP-1)*** inhibition was noted alongside the suppression of interferon regulatory factor 3(IRF3)phosphorylation and the expression of interferon-beta(IFN-β),C-X-C motif chemokine ligand 10(CXCL10),and inflammatory mediators such as tumor necrosis factor-alpha(TNF-α)and interleukin-6(IL-6).The mechanism of action appeared to involve the TGP’s attenuation of the STING-IRF3 interaction,without affecting STING oligomerization,thereby inhibiting the activation of downstream signaling *** vivo,the TGP hindered the initiation of the cGAS-STING pathway by the STING agonist dimethylxanthenone-4-acetic acid(DMXAA)and exhibited promising therapeutic effects in a model of acute liver injury induced by lipopolysaccharide(LPS)and D-galactosamine(D-GalN).Our findings underscore the potential of the TGP as an effective inhibitor of the cGAS-STING pathway,offering a new treatment avenue for inflammatory and autoimmune diseases mediated by this pathway.

关键词： Total glucosides of gaeony cGAS-STING pathway Inflammation LPS/D-GalN STING inhibitor

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Advances and challenges in hydrogel microspheres for biomedical applications

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Biomaterials Translational 2024年第3期5卷 203-204页

作者： Yiting Lei Hélder A Santos Wenguo Cui Department of Orthopaedic Surgery The First Affiliated Hospital of Chongqing Medical UniversityChongqingChina Chongqing Municipal Health Commission key laboratory of Musculoskeletal Regeneration and Translational medicine ChongqingChina Orthopaedic Research laboratory of Chongqing Medical University ChongqingChina Department of Biomaterials and Biomedical Technology The Personalized Medicine Research Institute(PRECISION)University Medical Center GroningenUniversity of GroningenGroningenthe Netherlands Drug Research Program Division of Pharmaceutical Chemistry and TechnologyFaculty of PharmacyUniversity of HelsinkiHelsinkiFinland Department of Orthopaedics Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint DiseasesShanghai Institute of Traumatology and OrthopaedicsRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiChina

Hydrogel microspheres,with their high water content and tunable physicochemical properties,have emerged as a promising class of materials for a myriad of biomedical applications.1 These microscale particles,which can be fabricated from both natural and synthetic polymers,exhibit diverse properties and bear a striking resemblance to the native extracellular matrix.2 This makes them highly suitable as substrates for cell culture,templates for tissue engineering,and vehicles for drug and protein delivery.

关键词： template striking microspheres

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