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Icaritin inhibits the progression of urothelial cancer by suppressing PADI2-mediated neutrophil infiltration and neutrophil extracellular trap formation

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Acta Pharmaceutica Sinica B 2024年第9期14卷 3916-3930页

作者： Zezhong Mou Yiling Chen Jinzhong Hu Yun Hu Lujia Zou Xinan Chen Shenghua Liu Qiuping Yin Jian Gong Shuchen Li Shanhua Mao Chenyang Xu Haowen Jiang Department of Urology Huashan HospitalFudan UniversityShanghai 200040China Fudan Institute of Urology Fudan UniversityShanghai 200040China National Clinical Research Center for Aging and Medicine Fudan UniversityShanghai 200040China

Tumor relapse and metastasis are the major causes of mortality associated with urothelial *** the tumor microenvironment,negative regulatory molecules and various immune cell subtypes suppress antitumor *** inflammatory microenvironment,associated with neutrophils and neutrophil extracellular traps(NETs),promotes tumor ***,no drugs are currently available to specifically inhibit neutrophils and *** this study,we first demonstrated that icaritin(ICT),a Chinese herbal remedy that is a first-line treatment for advanced and incurable hepatocellular carcinoma,reduces NETs caused by suicidal NETosis and prevents neutrophil infiltration in the tumor ***,ICT binds to and inhibits the expression of PADI2 in neutrophils,thereby suppressing PADI2-mediated histone ***,ICT inhibits ROS generation,suppresses the MAPK signaling pathway,and inhibits NET-induced tumor ***,ICT inhibits tumoral PADI2-mediated histone citrullination,which consequently suppresses the transcription of neutrophil-recruiting genes such as GM-CSF and *** downregulation of IL-6 expression,in turn,forms a regulatory feedback loop through the JAK2/STAT3/IL-6 *** a retrospective study of clinical samples,we found a correlation between neutrophils,NETs,UCa prognosis,and immune *** ICT with immune checkpoint inhibitors may have synergistic *** summary,our study demonstrated that ICT could be a novel inhibitor of NETs and a novel UCa treatment.

关键词： Icaritin neutrophil neutrophil extracellular trap PADI2 Urothelial cancer

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Shifting focus from bacteria to host neutrophil extracellular traps of biodegradable pure Zn to combat implant centered infection

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Bioactive Materials 2023年第3期21卷 436-449页

作者： Feng Peng Juning Xie Haiming Liu Yufeng Zheng Xin Qian Ruixiang Zhou Hua Zhong Yu Zhang Mei Li Medical Research Center Department of OrthopedicsGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou510080China School of Medicine South China University of TechnologyGuangzhou510006China WeiLun PET Center Department of Nuclear MedicineGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou510080China School of Materials Science and Engineering Peking UniversityBeijing100871China Department of Orthopaedics The Fifth Affiliated HospitalSoutherm Medical UniversityGuangzhou510009China

The widespread use of orthopedic implants to support or replace bones is increasingly threatened by the risk of incurable bacterial infections,impenetrable microbial biofilms,and irreversible antibiotic *** the past,the development of anti-infective biomaterials focused solely on direct antibacterial properties while ignoring the host’s immune *** by the clearance of infection by the innate neutrophil response and partici-pation in anti-infectious immunity of Zn ions,we report an innovative neutrophil extracellular traps(NETs)strategy,induced by biodegradable pure Zn,which achieved therapeutic efficacy toward biomaterial-related *** in vitro and in vivo data showed that pure Zn was favorable for NETs formation by promoting the release of DNA fibers and granule proteins in a reactive oxygen species(ROS)-dependent manner,thereby retraining and degrading bacteria with an efficiency of up to 99.5%.Transcriptome analysis revealed that cytoskeletal rearrangement and toll-like receptor(TLR)signaling pathway were also involved in Zn-induced NETs ***,the in vivo results of a Staphylococcus aureus(***)-infected rat model veri-fied that pure Zn potentiated the bactericidal capability of neutrophils around implants,and promoted osseointegration in ***-infected rat *** antibacterial immunity concept lays a foundation for the development of other antibacterial biomaterials and holds great promise for treating orthopedic infections.

关键词： neutrophil extracellular trap Antibacterial Zinc implant Orthopedic infection

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TatD DNases of African trypanosomes confer resistance to host neutrophil extracellular traps

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Science China(Life Sciences) 2021年第4期64卷 621-632页

作者： Kai Zhang Ning Jiang Hongyu Chen Naiwen Zhang Xiaoyu Sang Ying Feng Ran Chen Qijun Chen Key Laboratory of Livestock Infectious Diseases in Norheasi China Ministry of EducationKey Laboratory of ZoonosisCollege of Animal Science and Veterinary MedicineShenyang Agricultural UntiversinShemang 110866China The Research Unit for Pathogenic Mechanisms of Zoonotie Parasites Chinese Academy of Medical SciencesShenyang 110866 China

African trypanosomatid parasites escape host acquired immune responses through periodic antigenic variation of their surface *** this study,we describe a mechanism by which the parasites counteract innate immune *** Tat D DNases were identified in each of Trypanosoma evansi and Trypanosoma *** DNases are bivalent metal-dependent endonucleases localized in the cytoplasm and flagella of the parasites that can also be secreted by the *** enzymes possess conserved functional domains and have efficient DNA hydrolysis *** neutrophil extracellular traps(NETs)induced by the parasites could be hydrolyzed by native and recombinant Tat D *** disruption was prevented,and the survival rate of parasites was decreased,in the presence of the DNase inhibitor aurintricarboxylic *** data suggest that trypanosomes can counteract host innate immune responses by active secretion of Tat D DNases to degrade NETs.

关键词： Trypanosoma evansi Trypanosoma brucei Tat D DNase neutrophil extracellular trap DNA hydrolysis immune evasion

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Elevated neutrophil extracellular traps by HBV-mediated S100A9-TLR4/RAGE-ROS cascade facilitate the growth and metastasis of hepatocellular carcinoma

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Cancer Communications 2023年第2期43卷 225-245页

作者： Xi Zhan RuiWu Xue-Hua Kong Yan You Kun He Xiao-Yu Sun Yong Huang Wei-Xian Chen Liang Duan Department of Laboratory Medicine The Second Affiliated Hospital of Chongqing Medical UniversityChongqing 400000P.R.China Department of Laboratory Medicine The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016P.R.China Key Laboratory of Laboratory Medical Diagnostics Ministry of EducationDepartment of Laboratory MedicineChongqing Medical UniversityChongqing 400010P.R.China Department of Pathology The Second Affiliated Hospital of Chongqing Medical UniversityChongqing 400000P.R.China Department of Hepatobiliary Surgery The Second Affiliated Hospital of Chongqing Medical UniversityChongqing 400000P.R.China

Background:neutrophil extracellular traps(NETs)are considered significant contributors to cancer progression,especially ***,it is still unclear whether NETs are involved in hepatitis B virus(HBV)-related hepatocarcinogenesis and have potential clinical significance during evaluation and management for hepatocellular carcinoma(HCC).In this study,we aimed to investigate the functional mechanism of NETs in HBV-related hepatocarcinogenesis and their clinical ***:A total of 175 HCC patients with and without HBV infection and 58 healthy controls were enrolled in this *** weremeasured in tissue specimens,freshly isolated neutrophils and blood serum from these patients,and the correlation of circulating serum NETs levels with malignancy was *** mechanism by which HBV modulates NETs formation was explored using cell-based *** addition,in vitro and in vivo experiments were further performed to clarify the functional mechanism of NETs on the growth and metastasis of ***:We observed an elevated level of NETs in blood serum and tissue specimens from HCC patients,especially those infected with *** facilitated the growth and metastasis of HCC both in vitro and in vivo,which were mainly dominated by increased angiogenesis,epithelial-mesenchymal transition(EMT)-related cell migration,matrix metalloproteinases(MMPs)-induced extracellular matrix(ECM)degradation and NETs-mediated cell *** of NETs generation by DNase 1 effectively abrogated the NETs-aroused HCC growth and *** addition,HBV-induced S100A9 accelerated the generation of NETs,which was mediated by activation of toll-like receptor(TLR4)/receptor for advanced glycation end products(RAGE)-reactive oxygen species(ROS)***,circulatory NETs were found to correlate with viral load,TNM stage and metastasis status in HBV-related HCC,and the identified NETs could predict extrahepatic metastasis,with an area under the ROC curve(A

关键词： hepatocellular carcinoma hepatitis B virus metastasis neutrophil extracellular trap RAGE ROS S100A9 TLR4

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The Imbalance of Homeostasis in neutrophil extracellular traps is Associated with Portal Vein Thrombosis in Patients with Decompensated Cirrhosis

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Journal of Clinical and Translational Hepatology 2024年第12期12卷 1009-1019页

作者： Ming Han Yujia Liu Ying Cao Yue Zhang Yonghong Yan Shuwei Deng Xiaoxue Yuan Huichun Xing Yuan Huang Liuluan Zhu Beijing Key Laboratory of Emerging Infectious Diseases Institute of Infectious DiseasesBeijing Ditan HospitalCapital Medical UniversityBeijingChina Beijing Institute of Infectious Diseases BeijingChina National Center for Infectious Diseases Beijing Ditan HospitalCapital Medical UniversityBeijingChina Center of Liver Diseases Division 1 Beijing Ditan HospitalCapital Medical UniversityBeijingChina Department of Hepatobiliary and Pancreatic Medicine Beijing Tsinghua Changgung HospitalSchool of Clinical MedicineTsinghua UniversityBeijingChina Center of Liver Diseases Division 3 Beijing Ditan HospitalCapital Medical UniversityBeijingChina Peking University Ditan Teaching Hospital BeijingChina Digestive Department Beijing Tsinghua Changgung HospitalSchool of Clinical MedicineTsinghua UniversityBeijingChina

Background and Aims:Portal vein thrombosis(PVT)is a challenging complication in liver cirrhosis,with no currently available sensitive diagnostic *** study aimed to investigate the potential of neutrophil extracellular traps(NETs)and Deoxyribonuclease(DNase)as diagnostic indicators for PVT in chronic hepatitis B(CHB)-related decompensated ***:We analyzed 145 CHB-related decompensated cirrhosis patients from the Ditan study and 33 from the Changgung validation study,categorizing them based on PVT *** samples were assessed for NET markers,including cell-free DNA(cfDNA)and histone-DNA complexes,along with DNase ***:PVT patients exhibited elevated levels of cfDNA and histone-DNA complexes,and reduced DNase *** pattern persisted regardless of hepatocellular carcinoma(HCC)***-DNA levels,DNase activity,and hemoglobin were identified as independent risk factors for *** operating characteristic curve analysis revealed that high histone-DNA levels may serve as a potential diagnostic marker for PVT,with an area under the curve of 0.8628 in the Ditan study and 0.7521 in the Changgung *** combined with cfDNA and DNase activity,the area under the curve improved to 0.8774 in the Ditan study and 0.7975 in the Changgung ***:Imbalances in NET homeostasis are associated with PVT in CHB-related decompensated cirrhosis,including cases involving ***-DNA complexes,a significant risk factor for PVT,show potential as a diagnostic marker for PVT in decompensated cirrhosis,particularly in HBV-related HCC.

关键词： Portal vein thrombosis neutrophil extracellular trap Deoxyribonuclease Chronic hepatitis B Decompensated cirrhosis Hepatocellular carcinoma.

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Prmt1 upregulated by Hdc deficiency aggravates acute myocardial infarction via NETosis

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1840-1855页

作者： Zhiwei Zhang Suling Ding Zhe Wang Xiaowei Zhu Zheliang Zhou Weiwei Zhang Xiangdong Yang Junbo Ge Institutes of Biomedical Sciences and Shanghai Institute of Cardiovascular Diseases Zhongshan HospitalFudan UniversityShanghai 200032China Reproductive Medicine Centre Zhongshan HospitalFudan UniversityShanghai 200032China Department of Cardiology Zhongshan HospitalFudan UniversityShanghai 200032China NHC Key Laboratory of Viral Heart Diseases Fudan UniversityShanghai 200032China Key Laboratory of Viral Heart Diseases Chinese Academy of Medical SciencesShanghai 200032China

neutrophils are mobilized and recruited to the injured heart after myocardial infarction,and neutrophil count has been clinically implicated to be associated with coronary disease *** decarboxylase(HDC)has been implicated in regulating reactive oxidative species(ROS)and the differentiation of myeloid ***,the effect of HDC on neutrophils after myocardial infarction remains ***,we found that neutrophils were disorderly recruited into the ischemic injured area of the myocardium of Hdc deficiency(Hdc^(−/−))***,Hdc deficiency led to attenuated adhesion but enhanced migration and augmented ROS/neutrophil extracellular traps(NETs)production in ***^(−/−)mouse-derived NETs promoted cardiomyocyte death and cardiac fibroblast proliferation/***,protein arginine methyltransferase 1(PRMT1)was increased in Hdc^(−/−)mouse-derived neutrophils but decreased with exogenous histamine *** expression could be rescued by blocking histamine receptor 1(H1R),inhibiting ATP synthesis or reducing SWItch/sucrose non fermentable(SWI/SNF)chromatin remodeling ***,histamine or MS023 treatment could decrease ROS and NETs ex vivo,and ameliorated cardiac function and fibrosis,along with the reduced NETs in plasma in ***,our findings unveil the role of HDC in NETosis by histamine–H1R–ATP–SWI/SNF–PRMT1–ROS signaling and provide new biomarkers and targets for identifying and tuning the detrimental immune state in cardiovascular disease.

关键词： PRMT1 HDC Myocardial infarction neutrophil extracellular trap Transcriptomics Asymmetric demethylation arginine

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Applications of atomic force microscopy in immunology

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Frontiers of Medicine 2021年第1期15卷 43-52页

作者： Jiping Li Yuying Liu Yidong Yuan Bo Huang Beijing Smartchip Microelectronics Technology Company Limited Beijing 100192China Department of Immunology&National Key Laboratory of Medical Molecular Biology Institute of Basic Medical SciencesChinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijing 100005China Clinical Immunology Center Chinese Academy of Medical SciencesBeijing 100005China School of Microelectronics Tianjin UniversityTianjin 300072China Department of Biochemistry&Molecular Biology Tongji Medical CollegeHuazhong University of Science&TechnologyWuhan 430030China

Cellular mechanics,a major regulating factor of cellular architecture and biological functions,responds to intrinsic stresses and extrinsic forces exerted by other cells and the extracellular matrix in the *** mechanics also acts as a fundamental mediator in complicated immune responses,such as cell migration,immune cell activation,and pathogen *** principle of atomic force microscopy(AFM)and its three running modes are introduced for the mechanical characterization of living *** peak force tapping mode provides the most delicate and desirable virtues to collect high-resolution images of morphology and force *** a concrete description of AFM capabilities,three AFM applications are *** applications include the dynamic progress of a neutrophil-extracellular-trap release by neutrophils,the immunological functions of macrophages,and the membrane pore formation mediated by perforin,streptolysin O,gasdermin D,or membrane attack complex.

关键词： cellular mechanics atomic force microscopy neutrophil extracellular trap macrophage phagocytosis pore formation

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Hsa_circ_0036740 in familial adenomatous polyposis:Immune regulation and neutrophil effects in CRC based on highthroughput assay

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BIOCELL 2023年第11期47卷 2409-2422页

作者： ZHIWANG LI HAN YU YUPING LIU WEISHENG WU HAIJING ZENG EN LI Department of Gastrointestinal Surgery Meizhou People’s HospitalMeizhou514031China

Familial adenomatous polyposis(FAP)is an autosomal dominant disease with a high probability of becoming *** RNAs potentially associated with FAP have not been *** this study,a circRNA(circular RNA)expression profile of FAP was established using a circRNA microarray,and differentially expressed circRNAs were verified by *** effects of hsa_circ_0036740 on the malignant behavior of tumor cells(proliferation,apoptosis,and epithelial mesenchymal transition)and the levels of C3A complement protein expression were ***,neutrophils were isolated and co-cultured with colorectal cancer cells(CRCs),followed by measurements of MPO-DNA,citrullinated histone H3,interleukin(IL)-1β,IL-6,and IL-8 *** translocation of arginine deiminase 4(PAD4)was observed using immunofluorescence *** on the high-throughput assay,238 downregulated circRNAs,and 38 upregulated circRNAs were identified.A Kyoto Encyclopedia of Genes and Genomes enrichment analysis suggested that immune regulation might be involved in FAP.A total of 10 DECs(differentially expressed circular RNAs)were identified by RT-qPCR,and among them,hsa_circ_0036740 showed the highest fold-change in *** of gain-of-and loss-of-function studies revealed that hsa_circ_0036740 enhanced the malignant behavior of tumor cells,such as metastasis,proliferation,and apoptosis,with an increasing level of C3A ***,hsa_circ_0036740 also significantly increased neutrophil extracellular trap formation and inflammation in neutrophils,as shown by an increased expression of *** conclusion,this study revealed the expression profiles of circRNAs in FAP and confirmed the possible involvement of hsa_circ_0036740 in the immune regulation mediated by ***,hsa_circ_0036740 was suggested as a new therapeutic target for CRC.

关键词： Familial adenomatous polyposis Colorectal cancer Hsa_circ_0036740 neutrophil extracellular trap Metastasis

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Autophagy-mediated regulation of neutrophils and clinical applications

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Burns & Trauma 2020年第1期8卷 452-465页

作者： Yao Yu Bingwei Sun Department of Burns and Plastic Surgery the Affiliated Suzhou Hospital of Nanjing Medical UniversitySuzhou 215002Jiangsu ProvinceChina

Autophagy,an adaptive catabolic process,plays a cytoprotective role in enabling cellular homeostasis in the innate and adaptive immune ***,the most abundant immune cells in circulation,are professional killers that orchestrate a series of events during acute *** recent literature indicates that autophagy has important roles in regulating neutrophil functions,including differentiation,degranulation,metabolism and neutrophil extracellular trap formation,that dictate neutrophil *** is also becoming increasingly clear that autophagy regulation is critical for neutrophils to exert their immunological ***,evidence regarding the systematic communication between neutrophils and autophagy is ***,we provide an updated overview of the function of autophagy as a regulator of neutrophils and discuss its clinical relevance to provide novel insight into potentially relevant treatment strategies.

关键词： Autophagy neutrophil Innate immunity NETs Clinical application neutrophil extracellular trap

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A simple method for removing low-density granulocytes to purify T lymphocytes from peripheral blood mononuclear cells

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2017年第7期18卷 605-614页

作者： Si-gong ZHANG Yu-xin SONG Xiao-ming SHU Hai-li SHEN Han-bo YANG Rui-xue DUO Guo-chun WANG Department of Rheumatology Lanzhou University Second Hospital Department of Orthopaedics Gansu Provincial Hospital Department of Rheumatology China-Japan Friendship Hospital

Objective： Low-density granulocytes （LDGs） can form neutrophil extracellular traps （NETs） spontaneously and excessively. When peripheral blood mononuclear calls （PBMCs） are used for studying T lymphocytes, LDGs contained in the PBMCs may decrease the threshold of activating T lymphocytes by forming NETs. This study focused on the profiles of LDGs in common autoimmune diseases and methods for removing LDGs from PBMCs. Methods： The percentages of LDGs in PBMCs from 55 patients with dermatomyositis （DM）, 15 with polymyositis （PM）, 42 with rheumatoid arthritis （RA）, 25 with systemic lupus erythematosus （SLE）, and 19 healthy controls were determined by flow cytometry. Three methods of removing LDGs were explored and compared. After removal, PBMCs from six patients with positive *** were tested again to find out if LDGs contained in the PBMCs could influence T lymphocyte reactions. Results： Significantly higher LDG percentages were found in PBMCs from patients with DM （（8.41±10.87）%, P〈0.0001 ）, PM （（8.41±10.39）%, P〈0.0001 ）, RA （（4.05±6.97）%, P=0.0249）, and SLE （（7.53±11.52）%, P=0.0006）, compared with the controls （（1.28±0.73）%）. The *** values significantly decreased after LDGs were removed. Increasing relative centrifugal force （RCF） within a limited range can decrease the LDG percentage from an initial high level, but not markedly increase the LDG clearance rate. Compared with the whole blood sediment method, the PBMC adherence method can significantly remove LDGs yet scarcely influence the T lymphocyte percentage in PBMCs. Conclusions： The LDG percentage in PBMCs is significantly increased in patients with S/E, DM, PM, and RA. The influence of LDGs on T lymphocytes cannot be ignored in PBMC cultures. The adherence method is a simple and easy-to-use method for removing LDGs and purifying T lymphocytes from PBMCs.

关键词： Low-density granulocyte neutrophil extracellular trap Peripheral blood mononuclear cells Autoimmune disease T-SPOT. TB

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