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Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis

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Signal Transduction and Targeted Therapy 2024年第2期9卷 738-750页

作者： Yun Zhang Lijun Du Chenxi Wang Zhangsheng Jiang Qingchi Duan Yiping Li Zhijun Xie Zhixing He Yi Sun Lin Huang Liwei Lu Chengping Wen Key Laboratory of Chinese medicine rheumatology of Zhejiang Province Research Institute of Chinese Medical Clinical Foundation and ImmunologyCollege of Basic Medical ScienceZhejiang Chinese Medical UniversityHangzhou 310053China Department of General Surgery Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhou 310016China Cancer Institute(Key Laboratory of Cancer Prevention and Intervention China National Ministry of Education)of the Second Affiliated Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhou 310029China Cancer Center of Zhejiang University Hangzhou 310029China Department of Pathology and Shenzhen Institute of Research and Innovation The University of Hong KongHong KongChina Chongqing International Institute for Immunology Chongqing 400038China

Systemic lupus erythematosus(SLE),a severe autoimmune disorder,is characterized by systemic inflammatory response,autoantibody accumulation and damage to organs.The dysregulation of double-negative(DN)T cells is considered as a crucial commander during SLE.Neddylation,a significant type of protein post-translational modification(PTM),has been well-proved to regulate T cell-mediated immune response.However,the function of neddylation in SLE is still unknown.Here,we reported that neddylation inactivation with MLN4924,a specific inhibitor of NEDD8-activating enzyme E1(NAE1),or genetic abrogation of Ube2m in T cells decreased DN T cell accumulation and attenuated murine lupus development.Further investigations revealed that inactivation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in DN T cells,contributing to the apoptosis of the accumulated DN T cells in lupus mice.Then double knockout(KO)lupus-prone mice(Ube2m-/-Bim-/-lpr)were generated and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus progression.Our findings identified that neddylation inactivation promoted Bim-mediated DN T cell apoptosis and attenuated lupus progression.Clinically,we also found that in SLE patients,the proportion of DN T cells was raised and their apoptosis was reduced.Moreover,compared to healthy groups,SLE patients exhibited decreased Bim levels and elevated Cullin1 neddylation levels.Meantime,the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from SLE patients.Altogether,our findings provide the direct evidence about the function of neddylation during lupus,suggesting a promising therapeutic approach for this disease.

关键词： inactivation double finding

Removal of pathogenic indicator microorganisms during partial nitrification:the role of free nitrous acid

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Frontiers of Environmental Science & Engineering 2024年第3期18卷 93-102页

作者： Jiaojiao Xu Xiaotian Chen Rui Tang Jingwei Feng Shoujun Yuan Wei Wang Zhen-Hu Hu Anhui Engineering Laboratory of Rural Water Environment and Resource School of Civil EngineeringHefei University of TechnologyHefei 230009China Hefei 168 High School Hefei 230025China Shanghai Key Laboratory of Materials Protection and Advanced Materials in Electric Power Shanghai University of Electric PowerShanghai 200090China

Digested wastewater contains pathogenic microorganisms and high ammonia concentrations,which can pose a potential risk to public health.Effective removal of pathogens and nitrogen is crucial for the post-treatment of digested wastewater.Partial nitrification-anammox is an energy-saving nitrogen removal process.Free nitrous acid(FNA),an intermediate product of partial nitrification,has the potential to inactivate microorganisms.However,the efficiency and mechanisms of FNA-related inactivation in pathogens during partial nitrification remains unclear.In this study,Enterococcus and Escherichia coli(E.coli)were selected to investigate the efficiency and mechanisms of FNA-related inactivation in partial nitrification process.The results revealed that 83%±13%and 59%±27%of E.coli and Enterococcus were removed,respectively,in partial nitrification process at FNA concentrations of 0.023−0.028 mg/L.When the concentration of FNA increased from 0 to 0.5 mg/L,the inactivation efficiencies of E.coli and Enterococcus increased from 0 to 99.9%and 89.9%,respectively.Enterococcus exhibited a higher resistance to FNA attack compared to E.coli.3D-laser scanning microscopy(3D-LSM)and scanning electron microscopy(SEM)revealed that FNA exposure caused the surface collapse of E.coli and Enterococcus,as well as visible pore formation on the surface of E.coli cells.4',6-Diamidino-2-phenylindole dihydrochloride n-hydrate(DAPI)/propidium iodide(PI)and biomolecule leakage confirmed that inactivation of E.coli and Enterococcus occurred due to breakdown of cell walls and cell membranes.These findings indicate that partial nitrification process can be used for the removal of residual pathogenic microorganisms.

关键词： Partial nitrification Free nitrous acid Pathogenic indicator microorganism inactivation Cell structure

Quantitative determination of the electron beam radiation dose for SARS-CoV-2 inactivation to decontaminate frozen food packaging

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Virologica Sinica 2022年第6期37卷 823-830页

作者： Zihao Wang Zhentao Liang Rongguo Wei Hongwei Wang Fang Cheng Yang Liu Songdong Meng Key Laboratory of Pathogenic Microbiology and Immunology Institute of MicrobiologyChinese Academy of SciencesBeijing100101China University of Chinese Academy of Sciences Beijing100049China Department of Clinical Laboratory The Fifth Affiliated Hospital of Guangxi Medical UniversityNanning530022China China Isotope and Radiaton Corporation Beijing100089China Changchun CNNC CIRC Radiation Technology Co. LTDChangchun130022China

The spread of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) from cold-chain foods to frontline workers poses a serious public health threat during the current global pandemic. There is an urgent need to design concise approaches for effective virus inactivation under different physicochemical conditions to reduce the risk of contagion through viral contaminated surfaces of cold-chain foods. By employing a time course of electron beam exposure to a high titer of SARS-CoV-2 at cold-chain temperatures, a radiation dose of 2 kGy was demonstrated to reduce the viral titer from 10^(4.5)to 0 median tissue culture infectious dose(TCID_(50))/mL. Next,using human coronavirus OC43(HCoV-OC43) as a suitable SARS-CoV-2 surrogate, 3 kGy of high-energy electron radiation was defined as the inactivation dose for a titer reduction of more than 4 log units on tested packaging materials. Furthermore, quantitative reverse transcription PCR(RT-qPCR) was used to test three viral genes,namely, E, N, and ORF1ab. There was a strong correlation between TCID50and RT-qPCR for SARS-CoV-2detection. However, RT-qPCR could not differentiate between the infectivity of the radiation-inactivated and nonirradiated control viruses. As the defined radiation dose for effective viral inactivation fell far below the upper safe dose limit for food processing, our results provide a basis for designing radiation-based approaches for the decontamination of SARS-CoV-2 in frozen food products. We further demonstrate that cell-based virus assays are essential to evaluate the SARS-CoV-2 inactivation efficiency for the decontaminating strategies.

关键词： Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) inactivation Electron beam radiation Food decontamination Cold-chain

The inactivation of bacteriophages MS2 and PhiX174 by nanoscale zero-valent iron:Resistance difference and mechanisms

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Frontiers of Environmental Science & Engineering 2022年第8期16卷 247-256页

作者： Rong Cheng Yingying Zhang Tao Zhang Feng Hou Xiaoxin Cao Lei Shi Peiwen Jiang Xiang Zheng Jianlong Wang School of Environment and Natural Resources Renmin University of ChinaBeijing 100872China China Water Environment Group Co.Ltd. Beijing 101101China Institute of Nuclear and New Energy Technology Tsinghua UniversityBeijing 100084China

Pathogenic enteric viruses pose a significant risk to human health.Nanoscale zero-valent iron(nZVI),a novel material for environmental remediation,has been shown to be a promising tool for disinfection.However,the existing research has typically utilized MS2 or f2 bacteriophages to investigate the antimicrobial properties of nZVI,and the resistance difference between bacteriophages,which is important for the application of disinfection technologies,is not yet understood.Here,MS2 and PhiX174 containing RNA and DNA,respectively,were used as model viruses to investigate the resistances to nZVI.The bacteriophage inactivation mechanisms were also discussed using TEM images,protein,and nucleic acid analysis.The results showed that an initial concentration of 10^(6)PFU/mL of MS2 could be completely inactivated within 240 min by 40 mg/L nZVI at pH 7,whereas the complete inactivation of PhiX174 could not be achieved by extending the reaction time,increasing the nZVI dosage,or changing the dosing means.This indicates that the resistance of phage PhiX174 to nZVI was much stronger than that of MS2.TEM images indicated that the viral particle shape was distorted,and the capsid shell was ruptured by nZVI.The damage to viral surface proteins in both phages was examined by three-dimensional fluorescence spectrum and sodium dodecyl sulfate polyacrylamide gel electrophoresis(SDS-PAGE).However,the nucleic acid analysis demonstrated that the nucleic acid of MS2,but not PhiX174,was destroyed.It indicated that bacteriophage inactivation was mainly attributed to the damage of nucleic acids.

关键词： Nanoscale zero-valent iron(nZVI) MS2 PhiΧ174 Resistance inactivation Pathogenic microorganisms

Heat inactivation of monkeypox virus

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Journal of Biosafety and Biosecurity 2022年第2期4卷 121-123页

作者： Christophe Batéjat Quentin Grassin Maxence Feher Damien Hoinard Jessica Vanhomwegen Jean-Claude Manuguerra India Leclercq Institut Pasteur Université Paris CitéUnité Environnement et Risques InfectieuxCellule d’Intervention Biologique d’Urgence(CIBU)F-75015 ParisFrance

Different kinds of media spiked with monkeypox virus(MPXV)were subjected to heat inactivation at different temperatures for various periods of time.The results showed that MPXV was inactivated in less than 5 min at 70℃and less than 15 min at 60℃,with no difference between viruses from the West African and Central African clades.The present findings could help laboratory workers to manipulate MPXV in optimal biosafety conditions and improve their protocols.

关键词： inactivation Monkeypoxvirus Heat Virus

inactivation of Cryptosporidium by ozone and cell ultrastructures

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Journal of Environmental Sciences 2010年第12期22卷 1954-1959页

作者： Zhilin Ran Shaofeng Li Junli Huang Yixing Yuan Chongwei Cui Craig Denver Williams School of Municipal & Environmental Engineering Harbin Institute of Technology Harbin 150090 China Department of Building & Environmental Engineering Shenzhen Polytechnic Institute Shenzhen 518055 China School of Applied Science University of Wolverhampton Wolverhampton WV1 1LY UK

The fluorescence staining method and scanning electron microscopy （SEM） were used to study the effect of ozone （O3） inactivating Cryptosporidium in water and cell ultrastructures variation to shed light on the mechanism of inactivation preliminarily. Results indicated that O3 had a stronger inactivating capability. When the concentration of O3 was above 3.0 mg/L and the contact time was up to 7 min, a significant inactivating effect could be achieved. The turbidity on inactivation effects was also found to be statistically significant in artificial water. With increases in turbidity, the inactivating effect decreased. inactivation rate improved with a temperature increase from 5 to 25℃, but decreased beyond this. The inactivating capability of O3 was found to be stronger under acidic than that under alkalic conditions. When the concentration of organic matter in the reaction system was increased, the competition between Cryptosporidium and organics with O3 probably took place, thereby reducing the inactivation rate. In addition, the cellular morphology of Cryptosporidium varied with different contact times. At zero contact time, cells were rotundity and sphericity, at 60 sec they became folded, underwent emboly, and burst at 480 sec, the cell membrane of Cryptosporidium shrinked and collapsed completely.

关键词： ozone inactivation Cryptosporidium ultrastructures

inactivation of FOXO1 induces T follicular cell polarization and involves angioimmunoblastic T cell lymphoma

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Cancer Biology & Medicine 2019年第4期16卷 743-755页

作者： Meifang Xu Fei Wang Hong Chen Lin Liu Wenwen Liu Yinghong Yang Qiaoling Zheng Lihong Zhang Xiaoxuan Li Suxia Lin Shengbing Zang Department of Pathology Fujian Medical University Union HospitalFuzhou 350001China Division of Pediatrics University of Texas MD Anderson Cancer CenterHoustonTX 77030USA Department of Pathology The First Affiliated Hospital of Fujian Medical UniversityFuzhou 350004China Department of Pathology Fujian Medical UniversityFuzhou 350004China Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineGuangzhou 510060China Department of Pathology Sun Yat-sen University Cancer CenterGuangzhou 510060China

Objective:Angioimmunoblastic T cell lymphoma(AITL)is an aggressive form of non-Hodgkin lymphoma derived from mature T cells.However,the underlying pathogenesis of AITL remains unresolved.We aimed to explore the role of FOXO1-mediated signaling in the tumorigenesis and progression of AITL.Methods:FOXO1 expression was assessed using immunohistochemistry on a total of 46 AITL tissue samples.Retroviruses encoding FOXO1 shRNA were used to knockdown FOXO1 expression in CD4^+T cells.Flow cytometric assays analyzed the proliferation and survival of FOXO1 knockdown CD4^+T cells.Furthermore,we performed adoptive T-cell transfer experiments to identify whether inactivation of FOXO1 induced neoplastic follicular-helper T(Tfh)cell polarization and function.Results:Patients with low FOXO1 protein levels were prone to have an advanced tumor stage(P=0.049),higher ECOG ps(P=0.024),the presence of bone marrow invasion(P=0.000),and higher IPI(P=0.035).Additionally,the survival rates of patients in the FOXO1 high-expression group were significantly better than those in the FOXO1 low-expression group(χ^2=5.346,P=0.021).We also observed that inactivation of FOXO1 increased CD4^+T cell proliferation and altered the survival and cell-cycle progression of CD4^+T cells.Finally,we confirmed that inactivation of FOXO1 induces Tfh cell programing and function.Conclusions:inactivation of FOXO1 in AITL plays a key role in the tumorigenesis and progression of AITL.We propose that FOXO1 expression could be a useful prognostic marker in AITL patients to predict poor survival,and to design appropriate therapeutic strategies.

关键词： Angioimmunoblastic T cell lymphoma FOXO1 inactivation differentiation

inactivation of Bacillus Subtilis by Atomic Oxygen Radical Anion

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Plasma Science and Technology 2007年第1期9卷 119-124页

作者：李龙春王莲于宙吕选忠李全新 School of Sciences Anhui Agricultural UniversityHefei 230026China Department of ChemistryUniversity of Science and Technology of ChinaHefei 230026China Department of Chemical Physics University of Science and Technology of ChinaHefei 230026China School of Life Sciences University of Science and Technology of ChinaHefei 230027China Department of Chemistry University of Science and Technology of ChinaHefei 230026China

UAtomic oxygen radical anion （O-） is one of the most active oxygen species, and has extremely high oxidation ability toward small-molecules of hydrocarbons. However, to our knowledge, little is known about the effects of O- on cells of micro-organisms. This work showed that O- could quickly react with the Bacillus subtilis cells and seriously damage the cell walls a s well as their other contents, leading to a fast and irreversible inactivation. SEM micrographs revealed that the cell structures were dramatically destroyed by their exposure to O-. The inactivation efficiencies of B. subtilis depend on the O- intensity, the initial population of cells and the treatment temperature, but not on the pH in the range of our investigation. For a cell concentration of 10^6 cfu/ml, the number of survived cells dropped from 10^6 cfu/ml to 10^3 cfu/ml after about five-minute irradiation by an O- flux in an intensity of 233 nA/cm^2 under a dry argon environment （30 ℃, 1 atm, exposed size： 1.8 cm^2）. The inactivation mechanism of micro-organisms induced by O- is also discussed.

关键词： atomic oxygen radical anion inactivation Bacillus subtilis cell structure SEM

Viral inactivation by irradiation rays

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Light(Science & Applications) 2023年第4期12卷 505-506页

作者： Kai-Kai Liu Chong-Xin Shan Henan Key Laboratory of Diamond Optoelectronic Materials and Devices School of Physics and MicroelectronicsZhengzhou UniversityZhengzhouChina

Viral infection can lead to serious illness and death around the world,as exemplified by the spread of COVID-19.Using irradiation rays can inactive virions through ionizing and non-ionizing effect.The application of light in viral inactivation and the underlying mechanisms are reviewed by the research group of Dayong Jin from University of Technology Sydney.

关键词： effect. inactivation death