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Josephin domain containing 2(JOSD2)promotes lung cancer by inhibiting LKB1(Liver kinase B1)activity

Signal Transduction and Targeted Therapy 2024年第2期9卷 693-708页

作者： Tao Yuan Chenming Zeng Jiawei Liu Chenxi Zhao Fujing Ge Yuekang Li Meijia Qian Jiamin Du Weihua Wang Yonghao Li Yue Liu Xiaoyang Dai Jianya Zhou Xueqin Chen Shenglin Ma Hong Zhu Qiaojun He Bo Yang institute of Pharmacology&Toxicology Zhejiang Province Key Laboratory of Anti-Cancer Drug ResearchCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Innovation institute for Artificial Intelligence in medicine Zhejiang UniversityHangzhou 311199China Ministry of Education Key Laboratory of Chinese Medicinal Plants Resource from Lingnan Research Center of Medicinal Plants Resource Science and EngineeringGuangzhou University of Chinese MedicineGuangzhou 510006China Center for Drug Safety Evaluation and Research of Zhejiang University Hangzhou 310058China Department of respiratory Disease Thoracic Disease CenterThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou 310006China Department of Oncology Hangzhou Cancer HospitalHangzhou 310002China Cancer Center of Zhejiang University HangzhouChina Engineering Research Center of Innovative Anticancer Drugs Ministry of EducationHangzhouChina

Non-small cell lung cancer(NSCLC)ranks as one of the leading causes of cancer-related deaths worldwide.Despite the prominence and effectiveness of kinase-target therapies in NSCLC treatment,these drugs are suitable for and beneficial to a mere~30%of NSCLC patients.Consequently,the need for novel strategies addressing NSCLC remains pressing.Deubiquitinases(DUBs),a group of diverse enzymes with well-defined catalytic sites that are frequently overactivated in cancers and associated with tumorigenesis and regarded as promising therapeutic targets.Nevertheless,the mechanisms by which DUBs promote NSCLC remain poorly understood.Through a global analysis of the 97 DUBs’contribution to NSCLC survival possibilities using The Cancer Genome Atlas(TCGA)database,we found that high expression of Josephin Domain-containing protein 2(JOSD2)predicted the poor prognosis of patients.Depletion of JOSD2 significantly impeded NSCLC growth in both cell/patient-derived xenografts in vivo.Mechanically,we found that JOSD2 restricts the kinase activity of LKB1,an important tumor suppressor generally inactivated in NSCLC,by removing K6-linked polyubiquitination,an action vital for maintaining the integrity of the LKB1-STRAD-MO25 complex.Notably,we identified the first small-molecule inhibitor of JOSD2,and observed that its pharmacological inhibition significantly arrested NSCLC proliferation in vitro/in vivo.Our findings highlight the vital role of JOSD2 in hindering LKB1 activity,underscoring the therapeutic potential of targeting JOSD2 in NSCLC,especially in those with inactivated LKB1,and presenting its inhibitors as a promising strategy for NSCLC treatment.

关键词： LKB1 inhibiting removing

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Paracrine function amplifies pro-tumor electrochemical signal within neuron-glioma synapses

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Science China(Life Sciences) 2024年第6期67卷 1318-1320页

作者： Yan Hu Peishan Hu Xiaozhong Peng Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE State Key Laboratory of BiotherapyWest China Second University HospitalSichuan UniversityChengdu 610041China Guangdong institute of Gastroenterology Department of General SurgeryGuangdong Provincial Key Laboratory of Colorectal and Pelvic Floor DiseasesThe Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhou 510655China Department of Molecular Biology and Biochemistry Institute of Basic Medical SciencesMedical Primate Research CenterNeuroscience CenterChinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijing 100730China State Key Laboratory of respiratory Health and Multimorbidity Institute of Basic Medical Sciences Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijing 100730China institute of Laboratory Animal Science Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100730China

Neuronal activity plays a pivotal role in various physiological processes,including tissue development,homeostasis,and adaptability.Advances in recent years have improved our understanding of neuronal activity in brain cancers,such as glioblastoma(GBM)and diffuse midline gliomas(DMG),which are among the most prevalent and lethal cancers affecting children and adults.Generally,the neurons regulate brain cancers via two routes.

关键词： glioma homeostasis function

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Lung health for all: Focus more on the cardiopulmonary risk in patients with COPD

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中华医学杂志(英文版) 2024年第13期137卷 2024 Jun 5页

作者： Chen Rongchang Yang Jiefu Guangzhou institute of respiratory Health (Stake Key Lab of respiratory Disease) The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China Shenzhen institute of respiratory Diseases Shenzhen People’s Hospital Shenzhen Guangdong China Department of Cardiology Beijing Hospital National Center of Gerontology Institute of Geriatric Medicine Chinese Academy of Medical Sciences Beijing China

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The SARS-CoV-2 spike protein induces lung cancer migration and invasion in a TLR2-dependent manner

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Cancer Communications 2024年第2期44卷 273-277页

作者： Mi-Jeong Kim Ji Young Kim Ji Hye Shin Juhee Son Yeeun Kang Soo-Kyung Jeong Duk-Hwan Kim Kyun-Hwan Kim Eunyoung Chun Ki-Young Lee Department of Immunology Samsung Biomedical Research InstituteSungkyunkwan University School of MedicineSuwonRepublic of Korea Research and Development Center CHA Vaccine InstituteSeongnam-siRepublic of Korea Department of Molecular Cell Biology Sungkyunkwan University School of MedicineSuwonRepublic of Korea Department of Precision medicine Sungkyunkwan University School of MedicineSuwonRepublic of Korea Department of Health Sciences and Technology Samsung Advanced Institute for Health Sciences&TechnologySamsung Medical CenterSungkyunkwan UniversitySeoulRepublic of Korea

Dear editor,Severe acute respiratory syndrome coronavirus2(SARS-CoV-2)infection can lead to severe outcomes in patients with cancer[1].It has been reported that patients with lung cancers disproportionately manifest severe COVID-19 with a high rate of hospitalization and death[2].Notably,the SARS-CoV-2 Spike(S)protein can induce hyper-inflammation in both epithelial cells and macrophages through toll-like receptor(TLR)1/TLR2 or TLR2/6-dependent nuclear factor-kappaB(NF-κB)path-way[3].However,molecular and cellular evidence on whether the SARS-CoV-2 virus affects the severity of lung cancer patients through TLR1/2 or TLR2/6 signaling remains unclear.

关键词： lung TLR2 invasion

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Experimental models for cancer brain metastasis

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Cancer Pathogenesis and Therapy 2024年第1期2卷 15-23页

作者： Zihao Liu Shanshan Dong Mengjie Liu Yuqiang Liu Zhiming Ye Jianhao Zeng Maojin Yao Guangzhou institute of respiratory Disease The First Affiliated Hospital of Guangzhou Medical UniversityChina State Key Laboratory of Respiratory DiseaseGuangzhouGuangdong 510182China Department of Medical Genetics and Cell Biology GMU-GIBH Joint School of Life SciencesGuangzhou Medical UniversityGuangzhouGuangdong 511436China Department of Microbiology Immunologyand Cancer BiologyUniversity of Virginia Health SystemCharlottesvilleVA 22908USA

Brain metastases are a leading cause of cancer-related mortality.However,progress in their treatment has been limited over the past decade,due to an incomplete understanding of the underlying biological mechanisms.Employing accurate in vitro and in vivo models to recapitulate the complexities of brain metastasis offers the most promising approach to unravel the intricate cellular and physiological processes involved.Here,we present a comprehensive review of the currently accessible models for studying brain metastasis.We introduce a diverse array of in vitro and in vivo models,including cultured cells using the Transwell system,organoids,microfluidic models,syngeneic models,xenograft models,and genetically engineered models.We have also provided a concise summary of the merits and limitations inherent to each model while identifying the optimal contexts for their effective utilization.This review serves as a comprehensive resource,aiding researchers in making well-informed decisions regarding model selection that align with specific research questions.

关键词： Brain metastases Blood-brain barrier Animal model In vitro model

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Investigating the Mechanism of Qu Du Qiang Fei 1 Hao Fang Formula against Coronavirus Disease 2019 Based on Network Pharmacology Method

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World Journal of Traditional Chinese medicine 2024年第1期10卷 93-103页

作者： Yuan-Hua Wang He-Yang Zhou Jin-Yun Ma Gui-Qing Ding Hua Yu Yong-Sheng Jin Xiao-Dong Cheng institute of Clinical Immunology Yue-Yang Hospital of Integrative MedicineShanghai University of Traditional Chinese MedicineShanghaiChina School of Pharmacy Naval Medical UniversityShanghaiChina

Objective:Qu Du Qiang Fei 1 Hao Fang(QDQF1)is a novel Chinese herbal medicine formula used to treat coronavirus disease 2019(COVID-19).However,the pharmacological mechanisms of action of QDQF1 remain unclear.The objective of this study was to identify the effective ingredients and biological targets of QDQF1 for COVID-19 treatment.Materials and Methods:The effective ingredients and mechanisms of action of QDQF1 were analyzed by using network pharmacology methods,which included an analysis of the effective ingredients and corresponding targets,COVID-19-related target acquisition,compound-target network analyses,protein-protein interaction network analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)and Gene Ontology(GO)enrichment analyses,and molecular docking studies.Results:In total,288 effective QDQF1 ingredients were identified.We identified 51 core targets from the 148 targets through an overlap between putative QDQF1 targets and COVID-19-related targets.Six key components,including formononetin,kaempferol,luteolin,naringenin,quercetin,and wogonin were identified through component-target network analyses.GO functional enrichment analysis of the core targets revealed 1296 items,while KEGG pathway enrichment analysis identified 148 signaling pathways.Nine central targets(CCL2,CXCL8,IL1B,IL6,MAPK1,MAPK3,MAPK8,STAT3,and TNF)related to the COVID-19 pathway were identified in the KEGG pathway enrichment analysis.Furthermore,molecular docking analysis suggested that the docking scores of the six key components to the nine central targets were better than those to remdesivir.Conclusions:QDQF1 may regulate multiple immune-and inflammation-related targets to inhibit the progression of severe acute respiratory syndrome coronavirus 2,and thus,may be suitable for the treatment of COVID-19.

关键词： Coronavirus disease 2019 molecular docking molecular mechanism network pharmacology Qu Du Qiang Fei 1 Hao Fang formula

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Bispecific antibody drug conjugates:Making 1+1>2

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Acta Pharmaceutica Sinica B 2024年第5期14卷 1965-1986页

作者： Yilin Gu Zhijia Wang Yuxi Wang Targeted Tracer Research and Development Laboratory Institute of Respiratory HealthFrontiers Science Center for Disease-Related Molecular NetworkNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China Frontiers Medical Center Tianfu Jincheng LaboratoryChengdu 610212China

Bispecific antibody‒drug conjugates(BsADCs)represent an innovative therapeutic category amalgamating the merits of antibody‒drug conjugates(ADCs)and bispecific antibodies(BsAbs).Positioned as the next-generation ADC approach,BsADCs hold promise for ameliorating extant clinical challenges associated with ADCs,particularly pertaining to issues such as poor internalization,off-target toxicity,and drug resistance.Presently,ten BsADCs are undergoing clinical trials,and initial findings underscore the imperative for ongoing refinement.This review initially delves into specific design considerations for BsADCs,encompassing target selection,antibody formats,and the linker–payload complex.Subsequent sections delineate the extant progress and challenges encountered by BsADCs,illustrated through pertinent case studies.The amalgamation of BsAbs with ADCs offers a prospective solution to prevailing clinical limitations of ADCs.Nevertheless,the symbiotic interplay among BsAb,linker,and payload necessitates further optimizations and coordination beyond a simplistic“1+1”to effectively surmount the extant challenges facing the BsADC domain.

关键词： Bispecific antibody drug conjugates Antibody drug conjugates Bispecific antibody Targeted therapy Safety HER2 EGFR

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Development and performance evaluation of a culture-independent nanopore amplicon-based sequencing method for accurate typing and antimicrobial resistance profiling in Neisseria gonorrhoeae

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Science China(Life Sciences) 2024年第2期67卷 421-423页

作者： Chi Zhang Lulu Zhang Feng Wang Yaling Zeng Liying Sun Di Wang Yamei Li Liqin Wang Junping Peng NHC Key Laboratory of Systems Biology of Pathogens Institute of Pathogen BiologyChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100176China Key Laboratory of respiratory Disease Pathogenomics Chinese Academy of Medical SciencesBeijing 100730China Shenzhen Center for Chronic Disease Control Shenzhen 518020China

Dear Editor,Bacterial antimicrobial resistance(AMR)poses a serious threat to global human health(Antimicrobial Resistance Collaborators,2022).Comprehensive profiling of AMR and accurate molecular typing are important for tracking and controlling the emergence and dissemination of antibiotic-resistant bacteria(Yahara et al.,2021).We previously developed a multiplex amplicon sequencing-based method for directly sequencing AMR-related loci in N.gonorrhoeae from clinical samples(Zhang et al.,2021).

关键词： gonorrhoeae resistance

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Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

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Signal Transduction and Targeted Therapy 2024年第1期9卷 105-149页

作者： Yumin Wang Jing Hu Shuang Wu Joshua S.Fleishman Yulin Li Yinshi Xu Wailong Zou Jinhua Wang Yukuan Feng Jichao Chen Hongquan Wang Department of respiratory and Critical Care medicine Aerospace Center HospitalPeking University Aerospace School of Clinical MedicineBeijing 100049PR China Department of Pathogen Biology School of Basic Medical SciencesTianjin Medical UniversityTianjin 300060PR China Department of Neurology Zhongnan Hospital of Wuhan UniversityWuhan 430000PR China Department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John’s UniversityQueensNY 11439USA Department of Outpatient Aerospace Center HospitalPeking University Aerospace School of Clinical MedicineBeijing 100049PR China Beijing Key Laboratory of Drug Target and Screening Research Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050PR China Department of Pancreatic Cancer Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin 300060PR China

Ferroptosis,a unique modality of cell death with mechanistic and morphological differences from other cell death modes,plays a pivotal role in regulating tumorigenesis and offers a new opportunity for modulating anticancer drug resistance.Aberrant epigenetic modifications and posttranslational modifications(PTMs)promote anticancer drug resistance,cancer progression,and metastasis.Accumulating studies indicate that epigenetic modifications can transcriptionally and translationally determine cancer cell vulnerability to ferroptosis and that ferroptosis functions as a driver in nervous system diseases(NSDs),cardiovascular diseases(CVDs),liver diseases,lung diseases,and kidney diseases.In this review,we first summarize the core molecular mechanisms of ferroptosis.Then,the roles of epigenetic processes,including histone PTMs,DNA methylation,and noncoding RNA regulation and PTMs,such as phosphorylation,ubiquitination,SUMOylation,acetylation,methylation,and ADP-ribosylation,are concisely discussed.The roles of epigenetic modifications and PTMs in ferroptosis regulation in the genesis of diseases,including cancers,NSD,CVDs,liver diseases,lung diseases,and kidney diseases,as well as the application of epigenetic and PTM modulators in the therapy of these diseases,are then discussed in detail.Elucidating the mechanisms of ferroptosis regulation mediated by epigenetic modifications and PTMs in cancer and other diseases will facilitate the development of promising combination therapeutic regimens containing epigenetic or PTM-targeting agents and ferroptosis inducers that can be used to overcome chemotherapeutic resistance in cancer and could be used to prevent other diseases.In addition,these mechanisms highlight potential therapeutic approaches to overcome chemoresistance in cancer or halt the genesis of other diseases.

关键词： diseases epigenetic overcome

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Light at night and lung cancer risk:A worldwide interdisciplinary and time-series study

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Chinese Medical Journal Pulmonary and Critical Care medicine 2024年第1期2卷 56-62页

作者： Runchen Wang Qixia Wang Jianfu Li Jianrong Zhang Shixuan Lyu Wenhao Chi Zhiming Ye Xuanzhuang Lu Ying Shi Yubin Wang Xinjian Wu Ruiyu Hu Mónica Pérez-Ríos Jianxing He Wenhua Liang Department of Thoracic Surgery and Oncology The First Affiliated Hospital of Guangzhou Medical UniversityState Key Laboratory of Respiratory DiseaseNational Clinical Research Center for Respiratory DiseaseGuangzhou Institute of Respiratory HealthGuangzhouGuangdong 510120China Department of respiratory Disease China State Key Laboratory of Respiratory Disease and National Clinical Research Center for Respiratory DiseaseThe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdong 510120China Centre for Cancer Research&Department of General Practice Faculty of MedicineDentistry and Health SciencesUniversity of MelbourneVictorian Comprehensive Cancer CentreMelbourneVictoria 3010Australia Department of Civil Engineering University of BristolBristolBS81TRUK Academy of Mathematics and Systems Science Chinese Academy of SciencesBeijing 100190China University of Chinese Academy of Sciences Beijing 100049China Nanshan School Guangzhou Medical UniversityGuangzhouGuangdong 511436China State Key Laboratory of Information Engineering in Surveying Mapping and Remote Sensing Wuhan UniversityWuhanHubei 430079China GNSS Research Center Wuhan UniversityWuhanHubei 430079China First Clinical School Guangzhou Medical UniversityGuangzhouGuangdong 511436China Preventive medicine and Public Health Department University of Santiago de CompostelaCIBER de Epidemiología y Salud Pública(CIBERESP)Health Research Institute of Santiago de Compostela(IDIS)Santiago de CompostelaGalicia 15782Spain Southern Medical University GuangzhouGuangdong 510515China

Background:Light at night(LAN)has become a concern in interdisciplinary research in recent years.This global interdisciplinary study aimed to explore the exposure-lag-response association between LAN exposure and lung cancer incidence.Methods:LAN data were obtained from the Defense Meteorological Satellite Program’s Operational Linescan System.Data of lung cancer incidence,socio-demographic index,and smoking prevalence of populations in 201 countries/territories from 1992 to 2018 were collected from the Global Burden of Disease Study.Spearman correlation tests and population-weighted linear regression analysis were used to evaluate the correlation between LAN exposure and lung cancer incidence.A distributed lag nonlinear model(DLNM)was used to assess the exposure-lag effects of LAN exposure on lung cancer incidence.Results:The Spearman correlation coefficients were 0.286-0.355 and the population-weighted linear regression correlation coefficients were 0.361-0.527.After adjustment for socio-demographic index and smoking preva-lence,the Spearman correlation coefficients were 0.264-0.357 and the population-weighted linear regression correlation coefficients were 0.346-0.497.In the DLNM,the maximum relative risk was 1.04(1.02-1.06)at LAN exposure of 8.6 with a 2.6-year lag time.After adjustment for socio-demographic index and smoking prevalence,the maximum relative risk was 1.05(1.02-1.07)at LAN exposure of 8.6 with a 2.4-year lag time.Conclusion:High LAN exposure was associated with increased lung cancer incidence,and this effect had a specific lag period.Compared with traditional individual-level studies,this group-level study provides a novel paradigm of effective,efficient,and scalable screening for risk factors.

关键词： Light at night Satellite imagery Lung cancer Distributed lag nonlinear model(DLNM) Melatonin

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