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Recent advances in Alzheimer’s disease:mechanisms,clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy 2024年第9期9卷 3907-3941页

作者： Jifa Zhang Yinglu Zhang Jiaxing Wang Yilin Xia Jiaxian Zhang Lei Chen Department of Neurology Laboratory of Neuro-system and Multimorbidity and State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610041 SichuanChina Department of Pharmaceutical Sciences College of PharmacyUniversity of Tennessee Health Science CenterMemphis 38163 TNUSA

Alzheimer’s disease(AD)stands as the predominant form of dementia,presenting significant and escalating global *** etiology is intricate and diverse,stemming from a combination of factors such as aging,genetics,and *** current understanding of AD pathologies involves various hypotheses,such as the cholinergic,amyloid,tau protein,inflammatory,oxidative stress,metal ion,glutamate excitotoxicity,microbiota-gut-brain axis,and abnormal ***,unraveling the interplay among these pathological aspects and pinpointing the primary initiators of AD require further elucidation and *** the past decades,most clinical drugs have been discontinued due to limited effectiveness or adverse ***,available drugs primarily offer symptomatic relief and often accompanied by undesirable side ***,recent approvals of aducanumab(1)and lecanemab(2)by the Food and Drug Administration(FDA)present the potential in disreasemodifying ***,the long-term efficacy and safety of these drugs need further ***,the quest for safer and more effective AD drugs persists as a formidable and pressing *** review discusses the current understanding of AD pathogenesis,advances in diagnostic biomarkers,the latest updates of clinical trials,and emerging technologies for AD drug *** highlight recent progress in the discovery of selective inhibitors,dual-target inhibitors,allosteric modulators,covalent inhibitors,proteolysis-targeting chimeras(PROTACs),and protein-protein interaction(PPI)*** goal is to provide insights into the prospective development and clinical application of novel AD drugs.

关键词： drugs clinical approval

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Resolving the developmental mechanisms of cardiac microthrombosis of SARS-CoV-2 based on single-cell transcriptome analysis

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Science China Life Sciences 2025年第01期 103-115页

作者： Xizi Luo Nan Zhang Yuntao Liu Beibei Du Xuan Wang Tianxu Zhao Bingqiang Liu Shishun Zhao Jiazhang Qiu Guoqing Wang state key laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Key Laboratory for Zoonosis Research of the Ministry of EducationCollege of Basic MedicineJilin University state key laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Key Laboratory for Zoonosis Research of the Ministry of EducationCollege of Veterinary MedicineJilin University College of Mathematics Jilin University Bioinformatic Lab School of MathematicsShandong University Department of Cardiology China-Japan Union HospitalJilin University

The coronavirus disease 2019（COVID-19） outbreak caused by the severe acute respiratory syndrome coronavirus-2（SARS-CoV-2） developed into a global health emergency. Systemic microthrombus caused by SARS-CoV-2 infection is a common complication in patients with COVID-19. Cardiac microthrombosis as a complication of SARS-CoV-2 infection is the primary cause of cardiac injury and death in patietns with severe COVID-19. In this study, we performed single-cell sequencing analysis of the right ventricular free wall tissue from healthy donors,patients who died during the hypercoagulable period of characteristic coagulation abnormality（CAC）, and patients who died during the fibrinolytic period of CAC. We collected 61,187 cells enriched in 24 immune cell subsets and 13 cardiac-resident cell subsets. We found that in the course of SARS-CoV-2 infected heart microthrombus, MYO1EhighRASGEF1Bhighmonocyte-derived macrophages promoted hyperactivation of the immune system and initiated the extrinsic coagulation pathway by activating chemokines CCL3, CCL5. This series of events is the main cause of cardiac microthrombi following SARS-CoV-2 infection. In a SARS-CoV-2 infected heart microthrombus, excessive immune activation is accompanied by an increase in cellular iron content, which in turn promotes oxidative stress and intensifies intercellular competition. This induces cells to alter their metabolic environment, resulting in increased sugar uptake via the glycosaminoglycan synthesis pathway. In addition, high levels of reactive oxygen species generated by elevated iron levels promote increased endogenous malondialdehyde synthesis in a subpopulation of cardiac endothelial cells. This exacerbates endothelial cell dysfunction and exacerbates the coagulopathy process.

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Analysis of severe human adenovirus infection outbreak in Guangdong Province,southern China in 2019

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Virologica Sinica 2022年第3期37卷 331-340页

作者： Wenkuan Liu Shuyan Qiu Li Zhang Hongkai Wu Xingui Tian Xiao Li Duo Xu Jing Dai Shujun Gu Qian Liu Dehui Chen Rong Zhou state key laboratory of respiratory Diseases National Clinical Research Center for Respiratory DiseaseGuangdong-Hong Kong-Macao Joint Laboratory of Respiratory Infectious DiseaseThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Institute of Respiratory HealthGuangzhou Medical UniversityGuangzhou510040China Scientific Research Center The First Affiliated Hospital of Guangdong Pharmaceutical UniversityGuangzhou510062China Bioland laboratory Guangzhou LaboratoryGuangzhou510320China

During 2018–2019,a severe human adenovirus(HAdV)infection outbreak occurred in southern ***,we screened 18 respiratory pathogens in 1704 children(≤14 years old)hospitalized with acute respiratory illness in Guangzhou,China,in *** total,151 patients had positive HAdV test results;34.4%(52/151)of them exhibited severe *** infection occurred throughout the year,with a peak in *** median patient age was 3.0(interquartile range:1.1–5.0)*** with severe HAdV infection exhibited increases in12 clinical indexes(P≤0.019)and decreases in four indexes(P≤0.007),compared with patients exhibiting nonsevere *** significant differences were found in age or sex distribution according to HAdV infection severity(P>0.05);however,the distributions of comorbid disease and HAdV co-infection differed according to HAdV infection severity(P0.05);the HAdV-7 isolate exhibited stronger virulence and infectivity,compared with HAdV-3(P<0.001).Overall,comorbid disease,HAdV co-infection,and high virulence and infectivity of HAdV-7 were critical risk factors for severe HAdV infection;these data can facilitate treatment,control,and prevention of HAdV infection.

关键词： Human adenovirus(HAdV) Human adenovirus type 7(HAdV-7) Severe illness Epidemiology Acute respiratory illness Virulence and infectivity Risk factor

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Food allergy and related risk factors in 2540 preschool children: an epidemiological survey in Guangdong Province, southern China

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World Journal of Pediatrics 2015年第3期11卷 219-225页

作者： Guang-Qiao Zeng Jia-Ying Luo Hui-Min Huang Pei-Yan Zheng Wen-Ting Luo Ni-Li Wei Bao-Qing Sun state key laboratory of respiratory Disease National Clinical Research Center for Respiratory DiseasesGuangzhou Institute of Respiratory DiseasesFirst Affiliated HospitalGuangzhou Medical UniversityGuangzhouChina

Background:Although the number of studies on allergic diseases in the general population of southern China is increasing,only a few have addressed food allergy(FA)in children in this *** present study aimed to investigate the prevalence,clinical manifestations,spectrum of allergens,and related risk factors of FA in preschool children in Guangdong Province,southern ***:A random cluster-sampling method was used to select 24 kindergartens from 12 cities in Guangdong *** parents or guardians of the children were requested to complete a questionnaire on general information and data regarding FA diagnosis and symptoms in the children and their first-degree ***,the Chi-square test,multivariate regression analysis,and Spearman's rank-order correlation coefficient analysis were performed to identify statistically significant ***:Analysis of 2540 valid questionnaires revealed an FA prevalence rate of 4%.Adverse food reactions were due to the consumption of shrimp(4.4%),crab(3.2%),mango(2.3%),cow's milk and dairy products(1.9%),and eggs(1.4%).Logistic regression analysis indicated that a history of FA and a history of allergic rhinitis in the first-degree relatives were the major factors leading to FA in ***:The incidence of FA in children in Guangdong Province is higher than that commonly *** individual's genetic background is an important risk factor for ***,mitigation of the impact of lifestyle and environmental factors should be carefully considered to reduce the incidence of childhood FA.

关键词： allergic rhinitis eczema epidemiology food allergy questionnaire

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CAR designs for solid tumors: overcoming hurdles and paving the way for effective immunotherapy

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Biophysics Reports 2023年第5期9卷 279-297页

作者： Yuanbin Cui Mintao Luo Chuanyuan Gu Yuxian He Yao Yao Peng Li China-New Zealand Joint laboratory of Biomedicine and health State Key Laboratory of Respiratory DiseaseCAS Key Laboratory of Regenerative Biology Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences University of California San Diego

Chimeric antigen receptor T cell(CAR-T) therapy has revolutionized immunotherapy by modifying patients’ immune cells genetically. By expressing CARs, these modified cells can specifically identify and eliminate tumor cells. The success of CAR-T therapy in hematological malignancies, such as leukemia and lymphoma, has been remarkable. Numerous studies have reported improved patient outcomes and increased survival rates. However, the application of CAR-T therapy in treating solid tumors faces significant challenges. Solid tumors possess complex microenvironments containing stromal cells, extracellular matrix components, and blood vessels. These factors can impede the infiltration and persistence of CAR-T cells within the tumor. Additionally, the lack of target antigens exclusively expressed on tumor cells raises concerns about off-target effects and potential toxicity. This review aims to discuss advancements achieved by CAR-T therapy in solid tumors and the clinical outcomes in the realm of solid tumors.

关键词： Immunotherapy Solid tumor Chimeric antigen receptor T cell

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Intranasal booster using an Omicron vaccine confers broad mucosal and systemic immunity against SARS-CoV-2 variants

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Signal Transduction and Targeted Therapy 2023年第5期8卷 2345-2353页

作者： Qian Wang Chenchen Yang Li Yin Jing Sun Wei Wang Hengchun Li Zhengyuan Zhang Si Chen Bo Liu Zijian Liu Linjing Shi Xiaolin Liu Suhua Guan Chunhua Wang Linbing Qu Ying Feng Xuefeng Niu Liqiang Feng Jincun Zhao Pingchao Li Ling Chen Nanshan Zhong state key laboratory of respiratory Disease Guangzhou Institute of Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouChina Guangzhou nBiomed Ltd. GuangzhouChina Guangzhou laboratory&Bioland laboratory GuangzhouChina Guangdong laboratory of Computational Biomedicine Guangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesGuangzhouChina University of Chinese Academy of Sciences BeijingChina

The highly contagious SARS-CoV-2 Omicron subvariants severely attenuated the effectiveness of currently licensed SARS-CoV-2 vaccines based on ancestral strains administered via intramuscular *** this study,we generated a recombinant,replication-incompetent human adenovirus type 5,Ad5-S-Omicron,that expresses Omicron BA.1 ***,but not intramuscular vaccination,elicited spike-specific respiratory mucosal IgA and residential T cell immune responses,in addition to systemic neutralizing antibodies and T cell immune responses against most Omicron *** tested intranasal Ad5-S-Omicron as a heterologous booster in mice that previously received intramuscular injection of inactivated ancestral *** addition to inducing serum broadly neutralizing antibodies,there was a significant induction of respiratory mucosal IgA and neutralizing activities against Omicron subvariants BA.1,BA.2,BA.5,BA.2.75,BF.7 as well as pre-Omicron strains Wildtype,Beta,and *** and mucosal neutralizing activities against recently emerged XBB,BQ.1,and BQ.1.1 could also be detected but were much *** lavage fluids from intranasal vaccination contained multimeric IgA that can bind to at least 10 spike proteins,including Omicron subvariants and pre-Omicron strains,and possessed broadly neutralizing *** vaccination using Ad5-S-Omicron or instillation of intranasal vaccinee’s nasal lavage fluids in mouse nostrils protected mice against Omicron *** together,intranasal Ad5-S-Omicron booster on the basis of ancestral vaccines can establish effective mucosal and systemic immunity against Omicron subvariants and multiple SARS-CoV-2 *** candidate vaccine warrants further development as a safe,effective,and user-friendly infection and transmission-blocking vaccine.

关键词： nasal immunity mucosal

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Transferrin receptor-targeted immunostimulant for photodynamic immunotherapy against metastatic tumors through β-catenin/CREB interruption

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4118-4133页

作者： Mengyi Yan Xiayun Chen Xiaotong Li Qianqian Liu Baixue Yu Yi Cen Wei Zhang Yibin Liu Xinxuan Li Ying Chen Tao Wang Shiying Li The Fifth Affiliated Hospital Guangdong Provincial Key Laboratory of Molecular Target&Clinical Pharmacologythe NMPA and State Key Laboratory of Respiratory Diseasethe School of Pharmaceutical SciencesGuangzhou Medical UniversityGuangzhou 511436China Department of Anesthesiology the Second Clinical School of Guangzhou Medical UniversityGuangzhou 511436China state key laboratory of respiratory Diseases Guangdong Key Laboratory of Vascular DiseasesGuangzhou Institute of Respiratory Healththe first Affiliated HospitalGuangzhou Medical UniversityGuangzhou 510120China Department of Pulmonary and Critical Care Medicine Zhujiang HospitalSouthern Medical UniversityGuangzhou 510280China

The immunosuppressive phenotype of tumor cells extensively attenuates the immune activation effects of traditional *** this work,a transferrin receptor(TfR)targeted immunostimulant(PTI)is fabricated for photodynamic immunotherapy against metastatic tumors by interrupting β-catenin signal *** synthesize PTI,the photosensitizer conjugated TfR targeting peptide moiety(Palmitic-K(PpIX)-HAIYPRH)is unitized to encapsulate the transcription interrupter of *** the one hand,the recognition of PTI and TfR can promote drug delivery into tumor cells to destruct primary tumors through photodynamic therapy and initiate an immunogenic cell death with the release of tumorassociated *** the other hand,PTI will interrupt the binding between b-catenin andcAMP response element-binding protein(CREB),regulating the gene transcription to downregulate programmed death ligand 1(PD-L1)while upregulating CeC motif chemokine ligand 4(CCL4).Furthermore,the elevated CCL4 can recruit the dendritic cells to present tumor-specific antigens and promote T cells activation and infiltration,and the downregulated PD-L1 can avoid the immune evasion of tumor cells and activate systemic anti-tumor immunity to eradicate lung *** work may inspire the development of antibody antibody-free strategy to activate systemic immune response in consideration of immunosuppressive conditions.

关键词： Transferrin receptor β-Catenin signal pathway Tumor targeting Photodynamic therapy Immunotherapy Immunogenic cell death Programmed death ligand 1 C-C motif chemokine ligand 4

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SARS-CoV-2 nucleocapsid protein triggers hyperinflammation via protein-protein interaction-mediated intracellular Cl^(−) accumulation in respiratory epithelium

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Signal Transduction and Targeted Therapy 2022年第8期7卷 3080-3092页

作者： Lei Chen Wei-Jie Guan Zhuo-Er Qiu Jian-Bang Xu Xu Bai Xiao-Chun Hou Jing Sun Su Qu Ze-Xin Huang Tian-Lun Lei Zi-Yang Huang Jincun Zhao Yun-Xin Zhu Ke-Nan Ye Zhao-Rong Lun Wen-Liang Zhou Nan-Shan Zhong Yi-Lin Zhang School of Life Sciences Sun Yat-sen UniversityGuangzhouChina state key laboratory of respiratory Disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Medical UniversityGuangzhouChina Department of Thoracic Surgery Guangzhou Institute for Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Medical UniversityGuangzhouChina Guangzhou laboratory GuangzhouChina

SARS-CoV-2,the culprit pathogen of COVID-19,elicits prominent immune responses and cytokine *** Cl^(−)is a crucial regulator of host defense,whereas the role of Cl^(−)signaling pathway in modulating pulmonary inflammation associated with SARS-CoV-2 infection remains *** using human respiratory epithelial cell lines,primary cultured human airway epithelial cells,and murine models of viral structural protein stimulation and SARS-CoV-2 direct challenge,we demonstrated that SARS-CoV-2 nucleocapsid(N)protein could interact with Smad3,which downregulated cystic fibrosis transmembrane conductance regulator(CFTR)expression via *** intracellular Cl^(−)concentration([Cl^(−)]i)was raised,resulting in phosphorylation of serum glucocorticoid regulated kinase 1(SGK1)and robust inflammatory *** or knockout of SGK1 abrogated the N protein-elicited airway ***,N protein promoted a sustained elevation of[Cl^(−)]i by depleting intracellular cAMP via upregulation of phosphodiesterase 4(PDE4).Rolipram,a selective PDE4 inhibitor,countered airway inflammation by reducing[Cl^(−)]*** findings suggested that Cl^(−)acted as the crucial pathological second messenger mediating the inflammatory responses after SARS-CoV-2 *** the Cl^(−)signaling pathway might be a novel therapeutic strategy for COVID-19.

关键词： inflammation respiratory epithelium

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A pair of SARS-CoV-2 nucleocapsid protein monoclonal antibodies shows high specificity and sensitivity for diagnosis

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Virologica Sinica 2022年第6期37卷 942-945页

作者： An-Kai Zhu Sa-Sa Li Shu-Pei Yu Zhao-Yong Zhang Huan Li Jing-Feng Li Shan-Shan Gao Heng Chen Jincun Zhao Run Shi Mingjian Lu Chaoyang Li Affiliated Cancer Hospital and Institute of Guangzhou Medical University State Key Laboratory of Respiratory DiseaseKey Laboratory for Cell Homeostasis and Cancer Research of Guangdong High Education InstituteGuangzhou510095China state key laboratory of respiratory Disease National Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory HealthThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou510182China Department of Interventional Radiology Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhou510095China

Dear Editor,Severe Acute respiratory Syndrome Coronavirus Type 2(SARS-CoV-2) is the pathogen of the coronavirus disease 2019(COVID-19), which has spread ***-CoV-2 is an enveloped virus belongs to the family of β-coronavirus(Xu et al., 2020). Its genome is a linear single-stranded positive-sense RNA about 30,000 nucleotides packed inside a virion with a diameter of 100 nm and a volume of about 10^(6)nm^(3)(Bar-On et al., 2020).

关键词： al. diagnosis specificity

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JunB condensation attenuates vascular endothelial damage under hyperglycemic condition

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Journal of Molecular Cell Biology 2023年第12期15卷 34-49页

作者： Xuxia Ren Zexu Cui Qiaoqiao Zhang Zhiguang Su Wei Xu Jinhui Wu Hao Jiang laboratory for Aging and Cancer Research Frontiers Science Center Disease-related Molecular NetworkState Key Laboratory of Respiratory Health and Multimorbidity and National Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China key laboratory of Gene Engineering of the Ministry of Education State Key Laboratory of BiocontrolSchool of Life SciencesSun Yat-sen UniversityGuangzhou 510275China Molecular Medicine Research Center West China HospitalSichuan UniversityChengdu 610041China Center of Geriatrics and Gerontology National Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China

Endothelial damage is the initial and crucial factor in the occurrence and development of vascular complications in diabetic patients,contributing to morbidity and *** hyperglycemia has been identified as a damaging effector,the detailed mechanisms remain *** this study,identified by ATAC-seq and RNA-seq,JunB reverses the inhibition of proliferation and the promotion of apoptosis in human umbilical vein endothelial cells treated with high glucose,mainly through the cell cycle and p53 signaling ***,JunB undergoes phase separation in the nucleus and in vitro,mediated by its intrinsic disordered region and DNA-binding *** localization and condensation behaviors are required for JunB-mediated proliferation and ***,our study uncovers the roles of JunB and its coacervation in repairing vascular endothelial damage caused by high glucose,elucidating the involvement of phase separation in diabetes and diabetic endothelial dysfunction.

关键词： hyperglycemia JunB phase separation endothelial damage

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