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Notch signaling pathway in cancer:from mechanistic insights to targeted therapies

Signal Transduction and Targeted Therapy 2024年第6期9卷 2527-2563页

作者： Qingmiao Shi Chen Xue Yifan Zeng Xin Yuan Qingfei Chu Shuwen Jiang Jinzhi Wang Yaqi Zhang Danhua Zhu Lanjuan Li State Key laboratory for Diagnosis and Treatment of infectious diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

Notch signaling,renowned for its role in regulating cell fate,organ development,and tissue homeostasis across metazoans,is highly conserved throughout *** Notch receptor and its ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences,typically necessitating receptor-ligand interaction to initiate classical Notch signaling *** evidence indicates that the Notch signaling pathway serves as both an oncogenic factor and a tumor suppressor in various cancer *** of this pathway promotes epithelial-mesenchymal transition and angiogenesis in malignancies,closely linked to cancer proliferation,invasion,and ***,the Notch signaling pathway contributes to maintaining stem-like properties in cancer cells,thereby enhancing cancer *** regulatory role of the Notch signaling pathway in cancer metabolic reprogramming and the tumor microenvironment suggests its pivotal involvement in balancing oncogenic and tumor suppressive ***,the Notch signaling pathway is implicated in conferring chemoresistance to tumor ***,a comprehensive understanding of these biological processes is crucial for developing innovative therapeutic strategies targeting Notch *** review focuses on the research progress of the Notch signaling pathway in cancers,providing in-depth insights into the potential mechanisms of Notch signaling regulation in the occurrence and progression of ***,the review summarizes pharmaceutical clinical trials targeting Notch signaling for cancer therapy,aiming to offer new insights into therapeutic strategies for human malignancies.

关键词： Notch invasion involvement

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Mitochondrial dysfunction: A promising therapeutic target for liver diseases

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Genes & diseases 2024年第3期11卷 324-337页

作者： Ping Chen Lichao Yao Mengqin Yuan Zheng Wang Qiuling Zhang Yingan Jiang Lanjuan Li Department of infectious diseases Renmin Hospital of Wuhan UniversityWuhanHubei 430060China State Key laboratory for Diagnosis and Treatment of infectious diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiang 310003China

The liver is an important metabolic and detoxification organ and hence demands a large amount of energy,which is mainly produced by the *** tissues of pa-tients with alcohol-related or non-alcohol-related liver diseases contain ultrastructural mito-chondrial lesions,mitochondrial DNA damage,disturbed mitochondrial dynamics,and compromised ATP *** of mitochondrial reactive oxygen species in-duces oxidative damage to mitochondrial proteins and mitochondrial DNA,decreases mito-chondrial membrane potential,triggers hepatocyte inflammation,and promotes programmed cell death,all of which impair liver *** DNA may be a poten-tial novel non-invasive biomarker of the risk of progression to liver cirrhosis and hepatocellular carcinoma in patients infected with the hepatitis B *** herein present a review of the mechanisms of mitochondrial dysfunction in the development of acute liver injury and chronic liver diseases,such as hepatocellular carcinoma,viral hepatitis,drug-induced liver injury,alcoholic liver disease,and non-alcoholic fatty liver *** review also discusses mito-chondrion-centric therapies for treating liver diseases.

关键词： Chronic diseases Liverdamage Mesenchymalstem cell Mitochondrial dysfunction Oxidativestress

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Astragaloside IV Alleviates Acute Liver Failure Induced by D-GalN/LPS by Upregulating Autophagy and Reducing Inflammation

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infectious Microbes & diseases 2024年第1期6卷 20-28页

作者： Meng Hong Wenwen Lian Ying Yang Zhi Chen State Key laboratory for Diagnosis and Treatment of infectious diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina

Acute liver failure(ALF)is a life-threatening condition that manifests in an extremely serious manner and progresses *** following study investigated the protective effect of astragaloside IV(AS-IV),a traditional Chinese drug,on ALF,and its underlying mechanisms,focusing on autophagy and inflammation *** were randomly divided into a saline group,a D-galactosamine and lipopolysac-charide(D-GalN/LPS)group and an AS-IV *** analysis,immunohistochemistry,cytometric bead array,high-throughput quantitative PCR,flow cytometry and Western analysis were used to assess inflammation and liver damage 5 hours after D-GalN/LPS *** IV treatment reduced mortality by alleviating D-GalN/LPS–induced hepatic damage and decreasing inflammation(decreasing Ly6c+monocyte levels,reducing inflammatory cytokines and increasing anti-inflammatory factors)as well as upregulating ***,PCR array was used to detect expression of autophagy-related genes,which demonstrated a Log2 fold change in gene expression between the AS-IV and D-GalN/LPS groups ranging from 1.19 to-3.53,with Tnfsf10 showing the largest alteration be-tween the two *** data suggest that AS-IV may alleviate ALF by upregulating autophagy and reducing inflammation,and it may therefore be an interesting drug for alleviating ALF.

关键词： astragaloside IV acute liver failure inflammation autophagy

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MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation

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Asian Journal of Pharmaceutical Sciences 2024年第1期19卷 119-134页

作者： Wenyi Chen Feiyan Lin Xudong Feng Qigu Yao Yingduo Yu Feiqiong Gao Jiahang Zhou Qiaoling Pan Jian Wu Jinfeng Yang Jiong Yu Hongcui Cao Lanjuan Li State Key laboratory for the Diagnosis and Treatment of infectious diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesNational Medical Center for Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Jinan Microecological Biomedicine Shandong laboratory Jinan 250117China Key laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury diseases of Zhejiang Province Hangzhou 310003China

Primary sclerosing cholangitis(PSC)is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis,with no curative treatment available,and liver transplantation is inevitable for end-stage *** placentalmesenchymal stem cell(hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis,inhibit collagen production and possess immunomodulatory properties in autoimmune liver ***,we prepared hpMSC-derived exosomes(Exo^(MSC))and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2^(−/−)mice and multicellular organoids established from PSC *** results showed that Exo^(MSC) ameliorated liver fibrosis in Mdr2^(−/−)mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis,and the percentage of CD4+IL-17A+T cells was reduced both in Exo^(MSC)-treated Mdr2^(−/−)mice(Mdr2^(−/−)-Exo)in vivo and Exo^(MSC)-treated Th17 differentiation progressed in ***,Exo^(MSC) improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular ***,our data demonstrate the antifibrosis effect of Exo^(MSC) in PSC disease by inhibiting Th17 differentiation,and ameliorating the Th17-induced microenvironment,indicating the promising potential therapeutic role of Exo^(MSC) in liver fibrosis of PSC or Th17-related diseases.

关键词： Mesenchymal stem cell Exosomes Primary sclerosing cholangitis Fibrosis Organoids Th17

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Longitudinal gut fungal alterations and potential fungal biomarkers for the progression of primary liver disease

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Science China(Life Sciences) 2024年第6期67卷 1183-1198页

作者： Shiman Jiang Lvwan Xu Yanfei Chen Zheyue Shu Longxian Lv Yuxi Zhao Kefan Bi Sisi Yang Qiangqiang Wang Lanjuan Li State Key laboratory for Diagnosis and Treatment of infectious diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China Division of Hepatobiliary and Pancreatic Surgery Department of SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003China

Liver disease,a major health concern worldwide,is a serious and progressive ***,we not only established a mouse model of DEN+CCl4-induced primary liver disease but also collected clinical human samples to investigate longitudinal alterations in the gut *** liver disease advanced,gut integrity was disrupted,and the mycobiota was disturbed in the mouse *** metabolites associated with hepatocellular carcinoma(HCC)differed from those associated with the cirrhotic phase as follows:levels of stercobilin and aflatoxin B1 dialcohol were reduced,while levels of triterpenoids,bafilomycin A1,and DHEA were increased in the HCC *** abundance of the phylum Chytridiomycota increased as the chronic liver disease progressed and was then replaced by the phylum Ascomycota in *** on the results from clinical human samples,the genus Candida(Ascomycota)(in humans)and the genus Kazachstania(Ascomycota)(in mice)occupied a dominant position in the HCC group,while other fungi were *** increased abundance of *** and depletion of *** may be hallmarks of the progression of liver cirrhosis to early ***,the administration of *** and *** in the LC-HCC progression could accelerate or retard the progression of ***,gut fungi have the potential to serve as a noninvasive clinical biomarker and even a treatment method.

关键词： gut mycobiome liver disease longitudinal studies hepatocarcinogenesis fungal biomarker

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Human Placental Mesenchymal Stem Cells Relieve Primary Sclerosing Cholangitis via Upregulation of TGR5 in Mdr2-/-Mice and Human Intrahepatic Cholangiocyte Organoid Models

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Research 2024年第2期2023卷 355-372页

作者： Qigu Yao Wenyi Chen Yingduo Yu Feiqiong Gao Jiahang Zhou Jian Wu Qiaoling Pan Jinfeng Yang Lingling Zhou Jiong Yu Hongcui Cao Lanjuan Li State Key laboratory for the Diagnosis and Treatment of infectious diseases Cllaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affliated HospitalZhejang University School of Medicine79 Qingchun Rd.Hangzhou 310003China National Clinical Research center for infectious diseases HangzhouChina Key laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury diseases of Zhejiang Province 79 Qingchun Rd.Hangzhou 310003China Jjinan Microecological Biomedicine Shandong laboratory Jinan 250117China

Primary sclerosing cholangitis(PSC)is a biliary disease accompanied by chronic inflammation of the liver and biliary *** stem cells(MSCs)are used to treat liver diseases because of their immune regulation and regeneration-promoting *** study was performed to explore the therapeutic potential of human placental MSCs(hP-MSCs)in PSC through the Takeda G protein-coupled receptor 5(TGR5)receptor *** tissues were collected from patients with PSC and healthy donors(n=4)for RNA sequencing and intrahepatic cholangiocyte organoid ***-MSCs were injected via the tail vein into Mdr2^(-/-),bile duct ligation(BDL),and 3,5-diethoxycarbonyl-1,4-dihydrocollidine(DDC)mouse models or co-cultured with organoids to confirm their therapeutic effect on biliary *** in bile acid metabolic profile were analyzed by liquid chromatography/tandem mass spectrometry(LC-MS/MS).Compared with healthy controls,liver tissues and intrahepatic cholangiocyte organoids from PSC patients were characterized by inflammation and cholestasis,and marked downregulation of bile acid receptor TGR5 ***-MSC treatment apparently reduced the inflammation,cholestasis,and fibrosis in Mdr2^(-/-),BDL,and DDC model *** activating the phosphatidylinositol 3 kinase/extracellular signal-regulated protein kinase pathway,hP-MSC treatment promoted the proliferation of cholangiocytes,and affected the transcription of downstream nuclear factorκB through regulation of the binding of TGR5 and Pellino3,thereby affecting the cholangiocyte inflammatory phenotype.

关键词： inflammation TGR5 Human

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Impact of short-term ambient air pollution exposure on the risk of severe COVID-19

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Journal of Environmental Sciences 2024年第1期135卷 610-618页

作者： Baihuan Feng Jiangshan Lian Fei Yu Dan Zhang Weizhen Chen QiWang Yifei Shen Guoliang Xie Ruonan Wang Yun Teng Bin Lou Shufa Zheng Yida Yang Yu Chen Department of laboratory Medicine The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310000China Key laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province Hangzhou 310000China Institute of laboratory Medicine Zhejiang UniversityHangzhou 310000China Department of infectious diseases The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310000China State Key laboratory for Diagnosis and Treatment of infectious diseases National Clinical Research Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious Diseasesthe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310000China

Ecological studies suggested a link between air pollution and severe COVID-19 outcomes,while studies accounting for individual-level characteristics are *** the present study,we aimed to investigate the impact of short-term ambient air pollution exposure on disease severity among a cohort of 569 laboratory confirmed COVID-19 patients admitted to designated hospitals in Zhejiang province,China,from January 17 to March 3,2020,and elucidate the possible biological processes involved using *** with mild cases,severe cases had higher proportion of medical conditions as well as unfavorable results in most of the laboratory tests,and manifested higher air pollution exposure *** exposure to air pollutants was associated with increased risk of severe COVID-19 with odds ratio(OR)of 1.89(95%confidence interval(CI):1.01,3.53),2.35(95%CI:1.20,4.61),2.87(95%CI:1.68,4.91),and 2.01(95%CI:1.10,3.69)for PM_(2.5),PM_(10),NO_(2)and CO,*** for NO_(2)remained significant in two-pollutant models after adjusting for other *** analysis showed 884 differentially expressed genes which mainly were enriched in virus clearance related biological processes between patients with high and low NO_(2)exposure levels,indicating that compromised immune response might be a potential underlying mechanistic *** findings highlight the impact of shortterm air pollution exposure,particularly for NO_(2),on COVID-19 severity,and emphasize the significance in mitigating the COVID-19 burden of commitments to improve air quality.

关键词： Air pollution COVID-19 Severity Transcriptomics Immune response

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A prognostic four-gene signature and a therapeutic strategy for hepatocellular carcinoma:Construction and analysis of a circRNA-mediated competing endogenous RNA network

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Hepatobiliary & Pancreatic diseases International 2024年第3期23卷 272-287页

作者： Hai-Yan Zhang Jia-Jie Zhu Zong-Ming Liu Yu-Xuan Zhang Jia-Jia Chen Ke-Da Chen Zhejiang Chinese Medical University Hangzhou 310053China Shulan International Medical College Zhejiang Shuren UniversityHangzhou 310015China State Key laboratory for Diagnosis and Treatment of infectious diseases National Clinical Research Center for Infectious DiseasesNational Medical Center for Infectious DiseasesCollaborative Innovation Center for Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China

Background:Hepatocellular carcinoma(HCC)has a poor long-term *** competition of circular RNAs(circRNAs)with endogenous RNA is a novel tool for predicting HCC *** on the alterations of circRNA regulatory networks,the analysis of gene modules related to HCC is ***:Multiple expression datasets and RNA element targeting prediction tools were used to construct a circRNA-microRNA-mRNA network in *** function,pathway,and protein interaction analyses were performed for the differentially expressed genes(DEGs)in this regulatory *** the proteinprotein interaction network,hub genes were identified and subjected to regression analysis,producing an optimized four-gene signature for prognostic risk stratification in HCC ***-HCC drugs were excavated by assessing the DEGs between the low-and high-risk groups.A circRNA-microRNA-hub gene subnetwork was constructed,in which three hallmark genes,KIF4A,CCNA2,and PBK,were subjected to functional enrichment ***:A four-gene signature(KIF4A,CCNA2,PBK,and ZWINT)that effectively estimated the overall survival and aided in prognostic risk assessment in the The Cancer Genome Atlas(TCGA)cohort and International Cancer Genome Consortium(ICGC)cohort was *** inhibitors,PI3K inhibitors,HDAC inhibitors,and EGFR inhibitors were predicted as four potential mechanisms of drug action(MOA)in high-risk HCC *** analysis has revealed that PBK,CCNA2,and KIF4A play a crucial role in regulating the tumor microenvironment by promoting immune cell invasion,regulating microsatellite instability(MSI),and exerting an impact on HCC ***:The present study highlights the role of the circRNA-related regulatory network,identifies a four-gene prognostic signature and biomarkers,and further identifies novel therapy for HCC.

关键词： Hepatocellular carcinoma circRNA-related ceRNA network Biomarker Least absolute shrinkage and selection operator Bioinformatics

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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

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Knowledge,Attitude,and Practice Towards Mpox and Associated Factors Among HIV-Infected Individuals—Beijing Municipality,China,2023

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China CDC weekly 2024年第7期6卷 109-117,I0001,I0002页

作者： Yue Gu Ruiqi Ren Jing Han Wenqing Bai Yuanyuan Zhang Haoliang Liu Zhaohe Li Chao Li Rui Song Lei Zhou Chinese center for Disease Control and Prevention BeijingChina National center for infectious diseases Beijing Ditan HospitalCapital Medical UniversityBeijingChina Beijing Key laboratory of Emerging infectious diseases Institute of Infectious DiseasesBeijing Ditan HospitalCapital Medical UniversityBeijingChina Nanjing Medical University Nanjing CityJiangsu ProvinceChina

Summary What is already known about this topic?Approximately 50%of patients with mpox are human immunodeficiency virus(HIV)-infected *** have shown that individuals with advanced HIV infection tend to have more severe... 详细信息

关键词： mortality Infect clinical

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