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Aryl hydrocarbon receptor:Linking environment to aging process in elderly patients with asthma

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Chinese medical Journal 2024年第4期137卷 382-393页

作者： Tianrui Yang Rongjun Wan Wei Tu Sai Nithin Avvaru Peisong Gao Division of Allergy and Clinical immunology Department of MedicineJohns Hopkins University School of MedicineBaltimoreMD 21224USA Department of Geriatric Medicine The First People’s Hospital of Yunnan ProvinceKunmingYunnan 650032China Department of Respiratory Medicine Xiangya HospitalCentral South UniversityChangshaHunan 410008China The State key laboratory of Respiratory Disease for Allergy Shenzhen Key Laboratory of Allergy and ImmunologyShenzhen University School of MedicineShenzhenGuangdong 518055China

Aging is a significant risk factor for various diseases,including asthma,and it often leads to poorer clinical outcomes,particularly in elderly *** is recognized that age-related diseases are due to a time-dependent accumulation of cellular damage,resulting in a progressive decline in cellular and physiological functions and an increased susceptibility to chronic *** effects of aging affect not only the elderly but also those of younger ages,posing significant challenges to global ***,understanding the molecular mechanisms associated with aging in different diseases is *** intriguing factor is the aryl hydrocarbon receptor(AhR),which serves as a cytoplasmic receptor and ligand-activated transcription factor and has been linked to the aging ***,we review the literature on several major hallmarks of aging,including mitochondrial dysfunction,cellular senescence,autophagy,mitophagy,epigenetic alterations,and microbiome ***,we provide an overview of the impact of AhR on these hallmarks by mediating responses to environmental exposures,particularly in relation to the immune ***,we explore how aging hallmarks affect clinical characteristics,inflammatory features,exacerbations,and the treatment of *** is suggested that AhR signaling may potentially play a role in regulating asthma phenotypes in elderly populations as part of the aging process.

关键词： Aging Environment Reactive oxygen species Senescence Aryl hydrocarbon receptor Asthma

A novel engineered IL-21 receptor arms T-cell receptor-engineered T cells(TCR-T cells)against hepatocellular carcinoma

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Signal Transduction and Targeted Therapy 2024年第5期9卷 2215-2230页

作者： Wei Zhu Zhiming Zhang Jinzhang Chen Xiaolan Chen Lei Huang Xiaoyong Zhang Xuan Huang Na Ma Weikang Xu Xuan Yi Xinyu Lu Xin Fu Siwei Li Guoheng Mo Yiyue Wang Guosheng Yuan Mengya Zang Qi Li Xiaotao Jiang Yajing He Sha Wu Yukai He Yongyin Li Jinlin Hou State key laboratory of Organ Failure Research Guangdong Provincial Key Laboratory of Viral Hepatitis ResearchDepartment of Infectious DiseasesNanfang HospitalSouthern Medical UniversityGuangzhouChina institute of Cellular Medicine Newcastle University Medical SchoolNewcastleUK Department of Pathology The First People’s Hospital of FoshanFoshanChina Dermatology Hospital Southern Medical UniversityGuangzhouChina Department of immunology School of Basic Medical SciencesSouthern Medical UniversityGuangzhouChina Microbiome Medicine Center Department of Laboratory MedicineZhujiang HospitalSouthern Medical UniversityGuangzhouChina key laboratory of Proteomics of Guangdong Province Demonstration Center for Experimental Education of Basic Medical Sciences of ChinaGuangzhouChina medical College of Georgia Augusta University112015th StreetAugustaGAUSA

Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma(HCC)are urgently *** common cytokine receptorγchain(γc)family cytokines such as IL-2,IL-7,IL-15 and IL-21 play fundamental roles in T cell development,differentiation and effector *** study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell *** antitumor function of AFP-specific T cell receptor-engineered T cells(TCR-T)was augmented by exogenous IL-21 in vitro and in ***-21 enhanced proliferation capacity,promoted memory differentiation,downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation.A novel engineered IL-21 receptor was established,and TCR-T armed with the novel engineered IL-21 receptors(IL-21R-TCR-T)showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ***-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in ***-21R-TCR-T exhibited a less differentiated,exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen *** novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic *** novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC.

关键词： hepatocellular TCR utilize

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

The crosstalk between enteric nervous system and immune system in intestinal development,homeostasis and diseases

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Science China(Life Sciences) 2024年第1期67卷 41-50页

作者： Xindi Wang Chenbo Ding Hua-Bing Li Shanghai institute of immunology State Key Laboratory of Oncogenes and Related GenesShanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai Jiao Tong University School of Medicine-Yale institute for Immune Metabolism Shanghai Jiao Tong University School of MedicineShanghai 200025China

The gut is the largest digestive and absorptive organ,which is essential for induction of mucosal and systemic immune responses,and maintenance of metabolic-immune *** intestinal components contain the epithelium,stromal cells,immune cells,and enteric nervous system(ENS),as well as the outers,such as gut microbiota,metabolites,and *** dyshomeostasis of intestinal microenvironment induces abnormal intestinal development and functions,even colon diseases including dysplasia,inflammation and *** recent studies have identified that ENS plays a crucial role in maintaining the immune homeostasis of gastrointestinal(GI)*** crosstalk between ENS and immune cells,mainly macrophages,T cells,and innate lymphoid cells(ILCs),has been found to exert important regulatory roles in intestinal tissue programming,homeostasis,function,and *** this review,we mainly summarize the critical roles of the interactions between ENS and immune cells in intestinal homeostasis during intestinal development and diseases progression,to provide theoretical bases and ideas for the exploration of immunotherapy for gastrointestinal diseases with the ENS as potential novel targets.

关键词： enteric nervous system macrophages T cells innate lymphoid cells neuro-immune interactions

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

Correlation between Combined Urinary Metal Exposure and Grip Strength under Three Statistical Models:A Cross-sectional Study in Rural Guangxi

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Biomedical and Environmental Sciences 2024年第1期37卷 3-18页

作者： LIANG Yu Jian RONG Jia Hui WANG Xue Xiu CAI Jian Sheng QIN Li Dong LIU Qiu Mei TANG Xu MO Xiao Ting WEI Yan Fei LIN Yin Xia HUANG Shen Xiang LUO Ting Yu GOU Ruo Yu CAO Jie Jing HUANG Chu Wu LU Yu Fu QIN Jian ZHANG Zhi Yong Department of Environmental and Occupational Health School of Public HealthGuangxi Medical UniversityNanning 530021GuangxiChina key laboratory of Tumor immunology and Microenvironmental Regulation Guilin Medical UniversityGuilin 541199GuangxiChina Department of Environmental Health and Occupational Medicine School of Public HealthGuilin Medical UniversityGuilin 541199GuangxiChina Guangxi Colleges and Universities key laboratory of Prevention and Control of Highly Prevalent Diseases Guangxi Medical UniversityNanning 530021GuangxiChina Guangxi key laboratory of Environment and Health Research Guangxi Medical UniversityNanning 530021GuangxiChina key laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education Guangxi Medical UniversityNanning 530021GuangxiChina Guangxi Health Commission key laboratory of Entire Lifecycle Health and Care Guilin Medical UniversityGuilin 541199GuangxiChina

Objective This study aimed to investigate the potential relationship between urinary metals copper(Cu),arsenic(As),strontium(Sr),barium(Ba),iron(Fe),lead(Pb)and manganese(Mn)and grip *** We used linear regression models,quantile g-computation and Bayesian kernel machine regression(BKMR)to assess the relationship between metals and grip *** In the multimetal linear regression,Cu(β=−2.119),As(β=−1.318),Sr(β=−2.480),Ba(β=0.781),Fe(β=1.130)and Mn(β=−0.404)were significantly correlated with grip strength(P<0.05).The results of the quantile g-computation showed that the risk of occurrence of grip strength reduction was−1.007(95%confidence interval:−1.362,−0.652;P<0.001)when each quartile of the mixture of the seven metals was *** kernel function regression model analysis showed that mixtures of the seven metals had a negative overall effect on grip strength,with Cu,As and Sr being negatively associated with grip strength *** the total population,potential interactions were observed between As and Mn and between Cu and Mn(P_(interactions) of 0.003 and 0.018,respectively).Conclusion In summary,this study suggests that combined exposure to metal mixtures is negatively associated with grip ***,Sr and As were negatively correlated with grip strength levels,and there were potential interactions between As and Mn and between Cu and Mn.

关键词： Urinary metals Handgrip strength Quantile g-computation Bayesian kernel machine regression

Application of total keratometry in ten intraocular lens power calculation formulas in highly myopic eyes

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Eye and Vision 2024年第2期10卷 22-30页

作者： Ling Wei Kaiwen Cheng Wenwen He Xiangjia Zhu Yi Lu Department of Ophthalmology and Eye institute Eye and ENT Hospital of Fudan UniversityShanghai 200031China key laboratory of Myopia(Fudan University)key laboratory of MyopiaShanghai key laboratory of Visual Impairment and Restoration National Health CommissionChinese Academy of Medical ScienceShanghai 200031China State key laboratory of medical Neurobiology Fudan UniversityShanghai 200031China

Background:The accuracy of using total keratometry(TK)value in recent IOL power calculation formulas in highly myopic eyes remained ***:Highly myopic patients who underwent uneventful cataract surgery were prospectively enrolled in this prospective comparative *** one month postoperatively,standard deviation(SD)of the prediction errors(PEs),mean and median absolute error(MedAE)of 103 highly myopic eyes were back-calculated and compared among ten formulas,including XGboost,RBF 3.0,Kane,Barrett Universal II,Emmetropia Verifying Optical 2.0,Cooke K6,Haigis,SRK/T,and Wang-Koch modifications of Haigis and SRK/T formulas,using either TK or standard keratometry(K)***:In highly myopic eyes,despite good agreement between TK and K(P>0.05),larger differences between the two were associated with smaller central corneal thickness(P0.05),which both presented smaller MedAEs than others(all P0.05),and statistically larger percentages than the other eight formulas(P<0.05).Conclusions:Highly myopic eyes with thinner corneas tend to have larger differences between TK and *** XGboost enhancement calculator and RBF 3.0 formula using TK showed the most promising outcomes in highly myopic eyes.

关键词： High myopia Total keratometry Cataract surgery IOL power calculation

Durable and enhanced immunity against SARS-CoV-2 elicited by manganese nanoadjuvant formulated subunit vaccine

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Signal Transduction and Targeted Therapy 2024年第1期9卷 47-50页

作者： Mengyu Guo Mingjing Cao Jiufeng Sun Ziwei Chen Xin Wang Lianpan Dai George F.Gao Yuliang Zhao Yaling Wang Chunying Chen CAS key laboratory for Biomedical Effects of Nanomaterials and Nanosafety&CAS Center for Excellence in Nanoscience National Center for Nanoscience and Technology of ChinaBeijingChina Guangdong Provincial institute of Public Health Guangdong Provincial Center for Disease Control and PreventionGuangzhouChina CAS key laboratory of Pathogen Microbiology and immunology Institute of MicrobiologyBeijingChina

Dear editor,Vaccines are the most efficient and effective means to prevent infectious diseases,but improving the long-term protective efficacy is still a major challenge in contemporary vaccine development.1 The waning immunity varies depending on the diversification of the pathogen and the number of booster doses.1 Strategies to overcome this warrant is using adjuvants that amplify the immune response,and drive the production of memory B and T cells or long-lived plasma cells that recognize the pathogen for durable protection.2–4 Although existing adjuvants have achieved promising results,research on generating durable protective immunity is lacking in promoting vaccine development and staying ahead of global pandemics such as coronavirus disease 2019(COVID-19).The precisely designed nanoadjuvants can enhance lymph node targeting and increase antigenpresenting cell(APCs)uptake,achieving the co-delivery of adjuvants and antigens and activating innate and adaptive immune responses.5 Previously,we reported a manganese nanoadjuvant(MnARK)and receptor-binding domain(RBD)monomer antigen formulated nanovaccine.6 MnARK transported antigens to lymph nodes,activated the STING pathway,elicited strong neutralizing abilities and increased immune memory T cell percentage against the infection of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).6 Regarding the long-term protection potential of MnARK for subunit vaccine development,we further explored the durable immune regulation abilities of MnARK to a SARS-CoV-2 RBD dimer antigen,which has been used in an approved COVID-19 subunit vaccine ZF2001 with aluminum adjuvant(alum).7,8 TEM result revealed that RBD dimer could interact with BSA on MnARK surface and epitope can be well preserved(Supplementary Fig.1a).The size and zeta potential of MnARK-RBD dimer nanovaccine was~58 nm and-14 mV,respectively(Supplementary Fig.1b,c).

关键词： manganese immunity protective

Activation of leukotriene B_(4)receptor 1 is a prerequisite for complement receptor 3-mediated antifungal responses of neutrophils

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Cellular & Molecular immunology 2024年第3期21卷 245-259页

作者： Yan Xin Sihan Xiong Linghong Zhou Xin Lin institute for immunology and School of Medicine Tsinghua University100084BeijingChina Tsinghua University-Peking University Center for Life Sciences 100084BeijingChina Department of Infectious Diseases Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency ResponseNational Medical Center for Infectious DiseasesHuashan HospitalFudan UniversityShanghai200040China

Invasive fungal infections are life-threatening,and neutrophils are vital cells of the innate immune system that defend against *** role of LTA4H-LTB_(4)-BLT1 axis in regulation of neutrophil responses to fungal infection remains poorly ***,we demonstrated that the LTA4H-LTB_(4)-BLT1 axis protects the host against Candida albicans and Aspergillus fumigatus,but not Cryptococcus neoformans infection,by regulating the antifungal activity of *** results show that deleting Lta4h or Blt1 substantially impairs the fungal-specific phagocytic capacity of ***,defective activation of the spleen tyrosine kinase(Syk)and extracellular signal-related kinase(ERK1/2)pathways in neutrophils accompanies this ***,BLT1 regulates CR3-mediated,β-1,3-glucan-induced neutrophil phagocytosis,while a physical interaction with CR3 with slight influence on its dynamics is *** findings thus demonstrate that the LTA4H-LTB_(4)-BLT1 axis is essential for the phagocytic function of neutrophils in host antifungal immune response against Candida albicans and Aspergillus fumigatus.

关键词： LTA4H BLT1 Phagocytosis Complement receptor 3 Fungi