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Genome-wide transcriptome analysis of porcine epidemic diarrhea virus virulent or avirulent strain-infected porcine small intestinal epithelial cells

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Virologica Sinica 2022年第1期37卷 70-81页

作者： Ouyang Peng Xiaona Wei Usama Ashraf Fangyu Hu Yongbo Xia Qiuping Xu Guangli Hu Chunyi Xue Yongchang Cao Hao Zhang State Key laboratory of Biocontrol Life Sciences SchoolSun Yat-sen UniversityGuangzhou510006China Wen's Group Academy Wen's Foodstuffs Group CoLtdXinxingGuangdong527400China State Key laboratory of Agricultural Microbiology Huazhong Agricultural UniversityWuhan430070China Guangdong Provincial Key laboratory of Malignant tumor Epigenetics and Gene Regulation Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou510120China

Porcine epidemic diarrhea virus(PEDV)is the main cause of diarrhea,vomiting,and mortality in pigs,which results in devastating economic loss to the pig industry around the *** recent years,the advent of RNAsequencing technologies has led to delineate host responses at late stages of PEDV infection;however,the comparative analysis of host responses to early-stage infection of virulent and avirulent PEDV strains is currently ***,using the BGI DNBSEQ RNA-sequencing,we performed global gene expression profiles of pig intestinal epithelial cells infected with virulent(GDS01)or avirulent(HX)PEDV strains for 3,6,and 12 *** was observed that over half of all significantly dysregulated genes in both infection groups exhibited a down-regulated expression *** enrichment analyses indicated that the differentially expressed genes(DEGs)in the GDS01 group were predominantly related to autophagy and apoptosis,whereas the genes showing the differential expression in the HX group were strongly enriched in immune responses/*** the DEGs,the functional association of TLR3 and IFIT2 genes with the HX and GDS01 strains replication was experimentally validated by TLR3 inhibition and IFIT2 overexpression systems in cultured ***3 expression was found to inhibit HX strain,but not GDS01 strain,replication by enhancing the IFIT2 expression in infected *** conclusion,our study highlights similarities and differences in gene expression patterns and cellular processes/pathways altered at the early-stage infection of PEDV virulent and avirulent *** findings may provide a foundation for establishing novel therapies to control PEDV infection.

关键词： Coronavirus Porcine epidemic diarrhea virus(PEDV) Virulence Transcriptome Apoptosis Autophagy Immunity

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Boosting synergism of chemo- and immunotherapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules

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Acta Pharmaceutica Sinica B 2024年第2期14卷 836-853页

作者： Ge Song Minghui Li Shumin Fan Mengmeng Qin Bin Shao Wenbing Dai Hua Zhang Xueqing Wang Bing He Qiang Zhang Beijing Key laboratory of Molecular Pharmaceutics and New Drug Delivery systems School of Pharmaceutical SciencesPeking UniversityBeijing 100191China State Key laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Department of Medical Oncology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education)Peking University Cancer HospitalBeijing 100142China

Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted *** is critical to inspire new potential to remodel the value of this classical therapeutic ***,we fabricate bisphosphonate coordination lipid nanogranules(BC-LNPs)and load paclitaxel(PTX)to boost the chemo-and immuno-therapeutic synergism of cytotoxic *** in BC-LNPs@PTX,a bisphosphonate to block mevalonate metabolism,works as both the structure and drug constituent in nanogranules,where alendronate coordinated with calcium ions to form the particle *** synergy of alendronate enhances the efficacy of paclitaxel,suppresses tumor metastasis,and alters the cytotoxic *** from the paclitaxel-induced apoptosis,the involvement of alendronate inhibits the mevalonate metabolism,changes the mitochondrial morphology,disturbs the redox homeostasis,and causes theaccumulation of mitochondrial ROS and lethal lipid peroxides(LPO).These factors finally trigger the ferroptosis of tumor cells,an immunogenic cell death mode,which remodels the suppressive tumor immune microenvironment and synergizes with ***,by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis,BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

关键词： Bisphosphonate coordinationlipid nanogranules Ferroptosis Mevalonatemetabolism Mitochondrial metabolism Nano-systematic biology

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Enhanced digestion inhibition and mucus penetration of F127-modified self-nanoemulsions for improved oral delivery

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Asian Journal of Pharmaceutical Sciences 2018年第4期13卷 326-335页

作者： Wenyi Song Yuting Yang Miaorong Yu Quanlei Zhu Mohammadali Soleimani Damaneh Haijun Zhong Yong Gan Department of Pharmacy Medical College of Nanchang University Shanghai Institute of Materia Medica Chinese Academy of Sciences University of Chinese Academy of Sciences Division of Anti-tumor Pharmacology State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of Sciences

Self-nanoemulsifying systems(SNEs) have excellent ability to improve the solubility ofpoorly water-soluble drugs(PWSD). However, SNEs are likely to be degraded in gastroin-testinal(GIT) when their surface is recognized by lipase/co-lipase enzyme complex, result-ing in rapid release and precipitation of encapsulated drugs. The precipitates are then cap-tured and removed by intestinal mucus, reducing the delivery efficacy of SNEs. Herein, theamphiphilic polymer Pluronic? F127 was incorporated into long and short-chain triglyc-erides(LCT, SCT) based SNEs to diminish the recognition and therefore minimized theirdegradation by enzymes and clearance by mucus. The SNEs were characterized in termsof particle size, zeta potential and stability. Ex vivo multiple particles tracking studies wereperformed by adding particle solution into fresh rat mucus. Cellular uptake of SNEs wereconducted by using E12 cells, the absorption and distribution in small intestine were alsostudied after oral administration in male Sprague-Dawley(SD) rats. The in vitro digestionrate of SNEs were found to be in following order SCT-SNE > SCT-F127-SNE > LCT-SNE > LCT-F127-SNE. Moreover, the LCT-F127-SNE was found to be most effective in enhancing cellularuptake, resulting in 3.5-fold, 2.1-fold and 1.7-fold higher than that of SCT-SNE, LCT-SNE andSCT-F127-SNE, respectively. After incubating the SNE with E12 cells, the LCT-F127-SNE ex-hibited the highest amount regarding both mucus penetration and cellular uptake, with anuptake amount number(via bicinchoninic acid(BCA) analysis) of 3.5-fold, 2.1-fold and 1.7-fold higher than that of SCT-SNE, LCT-SNE and SCT-F127-SNE, respectively. The in vivo results revealed that orally administered LCT-F127-SNE could significantly increase the bioavailability of Cyclosporine A(CsA), which was approximately 2.43-fold, 1.33-fold and 1.80-fold higher than that of SCT-SNE, SCT-F127-SNE and LCT-SNE, respectively. We address in this work that F127-modified SNEs have potentia

关键词： Self-nanoemulsifying system(SNEs) Oral absorption Enzymatic degradation Mucus penetration Pluronic^(■) F127

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BAG6 restricts pancreatic cancer progression by suppressing the release of IL33-presenting extracellular vesicles and the activation of mast cells

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Cellular & Molecular immunology 2024年第8期21卷 918-931页

作者： Bilal Alashkar Alhamwe Viviane Ponath Fahd Alhamdan Bastian Dörsam Clara Landwehr Manuel Linder Kim Pauck Sarah Miethe Holger Garn Florian Finkernagel Anna Brichkina Matthias Lauth Dinesh Kumar Tiwari Malte Buchholz Daniel Bachurski Sabrina Elmshäuser Andrea Nist Thorsten Stiewe Lisa Pogge von Strandmann Witold Szymański Vanessa Beutgen Johannes Graumann Julia Teply-Szymanski Corinna Keber Carsten Denkert Ralf Jacob Christian Preußer Elke Pogge von Strandmann Institute for tumor immunology Philipps-University35043MarburgGermany Core Facility Extracellular Vesicles Philipps-University35043MarburgGermany Department of Anesthesiology Critical Careand Pain MedicineCardiac Anesthesia DivisionBoston Children’s HospitalBostonUSA Department of immunology and Anaesthesia Harvard Medical SchoolBostonMAUSA Translational Inflammation Research Division&Core Facility for Single Cell Multiomics Philipps-University35043MarburgGermany Core Facility Bioinformatics Philipps-University35043MarburgGermany Clinic for Gastroenterology Endocrinology and MetabolismCenter for Tumor and Immune BiologyPhilipps-University35043MarburgGermany Institute of systems immunology Philipps-University35043MarburgGermany Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases(CECAD) University of CologneCologneGermany Institute of Molecular Oncology and Genomics Core Facility Member of the German Center for Lung Research(DZL)Philipps-University35043MarburgGermany Institute of Lung Health Justus Liebig University35392GiessenGermany Institute of Translational Proteomics&Core Facility Translational Proteomics Biochemical/Pharmacological CentrePhilipps-University35043MarburgGermany Institute of Pathology Philipps-University Marburg and University Hospital Marburg(UKGM)MarburgGermany Department of Cell Biology and Cell Pathology Philipps-University35043MarburgGermany

Recent studies reveal a critical role of tumor cell-released extracellular vesicles(EVs)in pancreatic cancer(PC)***,driver genes that direct EV function,the EV-recipient cells,and their cellular response to EV uptake remain to be ***,we studied the role of Bcl-2-associated-anthanogene 6(BAG6),a regulator of EV biogenesis for cancer *** used a Cre recombinase/LoxP-based reporter system in combination with single-cell RNA sequencing to monitor in vivo EV uptake and tumor microenvironment(TME)changes in mouse models for pancreatic ductal adenocarcinoma(PDAC)in a Bag6 pro-or deficient *** vivo data were validated using mouse and human organoids and patient *** data demonstrated that Bag6-deficient subcutaneous and orthotopic PDAC tumors accelerated tumor growth dependent on EV ***,this was attributed to mast cell(MC)activation via EV-associated *** MCs promoted tumor cell proliferation and altered the composition of the TME affecting fibroblast polarization and immune cell *** cell proliferation and fibroblast polarization were mediated via the MC secretome containing high levels of PDGF and *** with high BAG6 gene expression and high protein plasma level have a longer overall survival indicating clinical *** current study revealed a so far unknown tumor-suppressing activity of BAG6 in ***6-deficiency allowed the release of EV-associated IL33 which modulate the TME via MC activation promoting aggressive tumor *** depletion using imatinib diminished tumor growth providing a scientific rationale to consider imatinib for patients stratified with low BAG6 expression and high MC infiltration.

关键词： Pancreatic cancer EVs BAG6 Mast cells

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Myeloid-derived suppressor cells promote B-cell production of IgA in a TNFR2-dependent manner

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Cellular & Molecular immunology 2017年第7期14卷 597-606页

作者： Xia Xu Qinghong Meng Ulrike Erben Peigang Wang Rainer Glauben Anja A Kühl Hao Wu Chung Wah Ma Minghua Hu Yuanyuan Wang Wei Sun Junying Jia Xinyi Wu Wei Chen Britta Siegmund Zhihai Qin Key laboratory of Protein and Peptide Pharmaceuticals Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and ImmunologyInstitute of BiophysicsChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Medical Department for Gastroenterology Infectious Diseases and Rheumatology/Research Center ImmunoSciencesCampus Benjamin FranklinCharité-Universitätsmedizin BerlinBerlin 12200Germany Infinitus Chinese Herbal Immunity Research Centre Guangzhou 510665China Berlin Institute for Medical systems Biology Max Delbrück Center for Molecular Medicine Berlin-BuchBerlin 13125Germany

Myeloid-derived suppressor cells(MDSCs)are well known for their capacity to suppress antitumor T-cell responses,but their effects on B-cell function and antibody production remain ***,we found that MDSCs that accumulated around the germinal center in the spleen of tumor-bearing mice co-located with B *** the presence of MDSCs,the antibody reaction to a surrogate antigen was significantly enhanced in mice,especially the immunoglobulin(Ig)A ***-culture with MDSCs promoted both proliferation and differentiation of B cells into IgA-producing plasma cells in ***,the cross talk between MDSCs and B cells required cell-cell *** from tumor necrosis factor receptor(TNFR)2^(−/−)mice,but not from TNFR1^(−/−)mice,failed to promote B-cell *** investigation suggested that interleukin-10 and transforming growth factor-β1 were crucial for the MDSC-mediated promotion of IgA *** results demonstrate a novel mechanism of MDSC-mediated immune regulation during tumor growth.

关键词： B cells IgA MDSCs TNFR2

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Targeting a disintegrin and metalloprotease(ADAM)17-CD122 axis enhances CD8^(+)T cell effector differentiation and anti-tumor immunity

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Signal Transduction and Targeted Therapy 2024年第7期9卷 3097-3111页

作者： Lina Sun Anjun Jiao Haiyan Liu Renyi Ding Ning Yuan Biao Yang Cangang Zhang Xiaoxuan Jia Gang Wang Yanhong Su Dan Zhang Lin Shi Chenming Sun Aijun Zhang Lianjun Zhang Baojun Zhang Department of Pathogenic Microbiology and immunology School of Basic Medical SciencesXi’an Jiaotong UniversityXi’anShaanxi 710061China Institute of Infection and Immunity Translational Medicine InstituteXi’an Jiaotong University Health Science CenterXi’anShaanxi 710061China Key laboratory of Environment and Genes Related to Diseases Ministry of EducationXi’anShaanxi 710061China Xi’an Key laboratory of Immune Related Diseases Xi’anShannxi 710061China Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy Cancer InstituteXuzhou Medical UniversityXuzhouJiangsuChina Department of Pediatrics Qilu Hospital of Shandong UniversityJinanChina National Key laboratory of Immunity and Inflammation Suzhou Institute of Systems MedicineChinese Academy of Medical Sciences&Peking Union Medical CollegeSuzhou 215123 JiangsuChina Key laboratory of Synthetic Biology Regulatory Elements Suzhou Institute of Systems MedicineChinese Academy of Medical Sciences&Peking Union Medical CollegeSuzhou 215123 JiangsuChina

CD8^(+)T cell immune responses are regulated by multi-layer networks,while the post-translational regulation remains largely *** ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane ***,by targeting the sheddase A Disintegrin and Metalloprotease(ADAM)17,we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8^(+)T *** and proteomic analysis revealed the involvement of post-translational regulation in CD8^(+)T cells.T cellspecific deletion of ADAM17 led to a dramatic increase in effector CD8^(+)T cell differentiation and enhanced cytolytic effects to eliminate pathogens and ***,ADAM17 regulated CD8^(+)T cells through cleavage of membrane ***17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8^(+)T ***,inhibition of ADAM17 in CD8^(+)T cells improved the efficacy of chimeric antigen receptor(CAR)T cells in solid *** findings reveal a critical post-translational regulation in CD8^(+)T cells,providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity.

关键词： immunity stimulation involvement

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Targeted cancer therapies based on antibodies directed against epidermal growth factor receptor:status and perspectives

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Acta Pharmacologica Sinica 2007年第9期28卷 1476-1493页

作者： Zhenping ZHU Im Clone systems Incorporated,New York,NY 10014,USA ImClone systems Incorporated New York USA

Compelling experimental and clinical evidence suggests that epidermal growthfactor receptor (EGFR) plays an important role in the pathogenesis of a variety ofhuman cancers;thus,providing a strong rationale for the development of receptorantagonists as effective and specific therapeutic strategies for the treatment ofEGFR-expressing *** antibodies (mAb),owing to their highspecificity towards a given target,represent a unique class of novel cancertherapeutics.A number of anti-EGFR mAb are currently being developed in ourclinic,including two that have been approved by the United States Food andDrug Administration for the treatment of refractory metastatic colorectal cancer(mCRC) and squamous cell carcinomas of the head and neck (SCCHN).Cetuximab(Erbitux,IMC-C225),an IgG1 mAb,has demonstrated significant antitumor activity,both as a single agent and in combination with chemotherapeutics and radiation,in patients with refractory mCRC and SCCHN,***(Vectibix),an IgG2 mAb,has been approved as a single agent for the treatment ofpatients with refractory *** mAb,via blocking ligand/receptorinteractions,exert their biological activity via multiple mechanisms,includinginhibition of cell cycle progression,potentiation of cell apoptosis,inhibition ofDNA repair,inhibition of angiogenesis,tumor cell invasion and metastasis and,potentially,induction of immunological effector ***-EGFR anti-bodies have demonstrated good safety profiles and potent anticancer activity inour clinic and may prove to be efficacious agents in the treatment of a variety ofhuman malignancies.

关键词： wear particles osteolysis aseptic loosening doxycycline

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Lymph node-biomimetic scaffold boosts CAR-T therapy against solid tumor

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National Science Review 2024年第4期11卷 206-215页

作者： Ziyan Liao Jie Jiang Wei Wu Jiaqi Shi Yanfang Wang Yuejun Yao Tao Sheng Feng Liu Wei Liu Peng Zhao Feifei Lv Jie Sun Hongjun Li Zhen Gu National Key laboratory of Advanced Drug Delivery and Release systems College of Pharmaceutical Sciences Zhejiang University Key laboratory of Advanced Drug Delivery systems of Zhejiang Province College of Pharmaceutical SciencesZhejiang University Liangzhu laboratory Zhejiang University Bone Marrow Transplantation Center of the First Affiliated Hospital and Department of Cell Biology Zhejiang University School of Medicine Department of Medical Oncology The First Affiliated Hospital School of Medicine Zhejiang University Department of laboratory Medicine The First Affiliated Hospital Zhejiang University School of Medicine Department of Hepatobiliary and Pancreatic Surgery The Second Affiliated HospitalSchool of MedicineZhejiang University Jinhua Institute of Zhejiang University MOE Key laboratory of Macromolecular Synthesis and Functionalization of Ministry of Education Department of Polymer Science and EngineeringZhejiang University Department of General Surgery Sir Run Run Shaw Hospital School of Medicine Zhejiang University

The limited infiltration and persistence of chimeric antigen receptor(CAR)-T cells is primarily responsible for their treatment deficits in solid tumors. Here, we present a three-dimensional scaffold, inspired by the physiological process of T-cell proliferation in lymph nodes. This scaffold gathers the function of loading,delivery, activation and expansion for CAR-T cells to enhance their therapeutic effects on solid tumors. This porous device is made from poly(lactic-co-glycolic acid) by a microfluidic technique with the modification of T-cell stimulatory signals, including anti-CD3, anti-CD28 antibodies, as well as cytokines. This scaffold fosters a 50-fold CAR-T cell expansion in vitro and a 15-fold cell expansion in vivo. Particularly, it maintains long-lasting expansion of CAR-T cells for up to 30 days in a cervical tumor model and significantly inhibits the tumor growth. This biomimetic delivery strategy provides a versatile platform of cell delivery and activation for CAR-T cells in treating solid tumors.

关键词： drug delivery cell therapy bioinspired biomaterials cancer immunotherapy

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Proteomics of adjacent-to-tumor samples uncovers clinically relevant biological events in hepatocellular carcinoma

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National Science Review 2023年第8期10卷 88-104页

作者： Hongwen Zhu Youpei Lin Dayun Lu Shisheng Wang Yuejia Liu Liangqing Dong Qian Meng Jing Gao Yuqiu Wang Nixue Song Yuying Suo Li Ding Pei Wang Bing Zhang Daming Gao Jia Fan Qiang Gao Hu Zhou Department of Analytical Chemistry State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor ResearchShanghai Institute of Materia Medica Chinese Academy of Sciences 2. Department of Liver Surgery and TransplantationLiver Cancer InstituteZhongshan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Fudan University School of Chinese Materia Medica Nanjing University of Chinese Medicine Institutes for systems Genetics and NHC Key Lab of Transplant Engineering and immunology Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application West China Hospital Sichuan University University of Chinese Academy of Sciences Department of Medicine McDonnell Genome Institute Siteman Cancer Center Washington University Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai Lester and Sue Smith Breast Center Department of Molecular and Human Genetics Baylor College of Medicine State Key laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences

Normal adjacent tissues(NATs) of hepatocellular carcinoma(HCC) differ from healthy liver tissues and their heterogeneity may contain biological information associated with disease occurrence and clinical outcome that has yet to be fully evaluated at the proteomic level. This study provides a detailed description of the heterogeneity of NATs and the differences between NATs and healthy livers and revealed that molecular features of tumor subgroups in HCC were partially reflected in their respective NATs. Proteomic data classified HCC NATs into two subtypes(Subtypes 1 and 2), and Subtype 2 was associated with poor prognosis and high-risk recurrence. The pathway and immune features of these two subtypes were characterized. Proteomic differences between the two NAT subtypes and healthy liver tissues were further investigated using data-independent acquisition mass spectrometry, revealing the early molecular alterations associated with the progression from healthy livers to NATs. This study provides a high-quality resource for HCC researchers and clinicians and may significantly expand the knowledge of tumor NATs to eventually benefit clinical practice.

关键词： proteomics hepatocellular carcinoma normal tissue adjacent to tumor heterogeneity

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Evaluation of tumor response to cytokine-induced killer cells therapy in malignant solid tumors

Evaluation of tumor response to cytokine-induced killer cell...

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第九届全国免疫学学术大会

作者： Xiao-Dong Li Binfeng Lu Changping Wu Jingting Jiang Department of tumor Biological Treatment The Third Affiliated Hospital of Soochow University Department of immunology University of Pittsburgh School of Medicine

CIK cells therapy has been evaluated as an adoptive cell immunotherapy for cancer patients,but there still have not been any standardized systems for evaluating the antitumor efficacy *** WHO and RECIST criteria have already been established for a few years but not sufficient to fully characterize the activity of *** on these two criteria,the irRC was proposed for evaluating the efficacy of immunotherapy.A variety of bioassays for immune monitoring including the specific and non-specific methods,have been *** recommend detect levels of various immunocytes,immune molecules and soluble molecules to find the correlations among them and clinicopathological characteristics to establish criteria for immunological *** also recommend a paradigm shift for the oncologists in the evaluation of immune therapies to ensure assessment of activity based on clinically relevant criteria and time points.

关键词： CIK cells therapy tumor response evaluation system

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