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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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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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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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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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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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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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Hypertension and NAFLD risk:Insights from the NHANES 2017-2018 and Mendelian randomization analyses

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Chinese Medical Journal 2024年第4期137卷 457-464页

作者： Mengqin Yuan Jian He Xue Hu Lichao Yao Ping Chen Zheng Wang Pingji Liu Zhiyu Xiong Yingan Jiang Lanjuan Li Department of infectious diseases Renmin Hospital of Wuhan UniversityWuhanHubei 430000China Department of Gastroenterology Nanfang HospitalSouthern Medical UniversityGuangzhouGuangdong 510010China state key laboratory for diagnosis and treatment of infectious diseases National Clinical Research Centre for Infectious DiseasesCollaborative Innovation Centre for Diagnosis and Treatment of Infectious DiseasesDepartment of Infectious DiseasesThe First Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouZhejiang 310000China

Background:Hypertension and non-alcoholic fatty liver disease(NAFLD)share several pathophysiologic risk factors,and the exact relationship between the two remains *** study aims to provide evidence concerning the relationship between hypertension and NAFLD by analyzing data from the National Health and Nutrition Examination Survey(NHANES)2017-2018 and Mendelian randomization(MR)***:Weighted multivariable-adjusted logistic regression was applied to assess the relationship between hypertension and NAFLD risk by using data from the NHANES ***,a two-sample MR study was performed using the genome-wide association study(GWAS)summary statistics to identify the causal association between hypertension,systolic blood pressure(SBP),diastolic blood pressure(DBP),and *** primary inverse variance weighted(IVW)and other supplementary MR approaches were conducted to verify the causal association between hypertension and *** analyses were adopted to confirm the robustness of the ***:A total of 3144 participants were enrolled for our observational study in *** multivariable-adjusted logistic regression analysis suggested that hypertension was positively related to NAFLD risk(odds ratio[OR]=1.677;95%confidence interval[CI],1.159-2.423).SBP≥130 mmHg and DBP≥80 mmHg were also significantly positively correlated with ***,hypertension was independently connected with liver steatosis(β=7.836[95%CI,2.334-13.338]).The results of MR analysis also supported a causal association between hypertension(OR=7.203[95%CI,2.297-22.587])and *** results were observed for the causal exploration between SBP(OR=1.024[95%CI,1.003-1.046]),DBP(OR=1.047[95%CI,1.005-1.090]),and *** sensitive analysis further confirmed the robustness and reliability of these findings(all P>0.05).Conclusion:Hypertension was associated with an increased risk of NAFLD.

关键词： Hypertension Non-alcoholic fatty liver disease National Health and Nutrition Examination Survey Mendelian randomization analysis Causality

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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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Current epidemiologic features and health dynamics of ESBL-producing Escherichia coli in China

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Biosafety and Health 2024年第1期6卷 40-49页

作者： Sayed Salman Zeeshan Umar Yonghong Xiao Collaborative Innovation Center for diagnosis and treatment of infectious diseases State Key Laboratory for Diagnosis and Treatment of Infectious Diseasesthe First Afiliated Hospital College of MedicineZhejiang UniversityHangzhou 310000China Marshall laboratory of Biomedical Engineering School of MedicineShenzhen UniversityShenzhen 510000China

Extended‐spectrumβ‐lactamase(ESBL)‐producing Escherichia coli(***)are widespread in China,with occurrences documented in humans,animals,and the *** dissemination of ESBL‐producing *** is likely facilitated by the widespread use of antibiotics in human and animal agriculture,the presence of antibiotic‐resistant bacteria(ARBs)in animal feces,and close human‐animal ***,particularly those belonging to incompatibility(Inc)group,such as IncF,IncI,and IncH families,play a vital role in facilitating the horizontal gene transfer of ESBL genes across various sectors,from humans to animals and the *** 26 and IS 1 elements also significantly influences the mobilization and evolution of antibiotic‐resistance genes(ARGs),contributing to the spread of ESBL‐producing ***‐M-14,blaCTX-15,and blaCTX‐M-55 are prevalent in ESBL‐producing *** across the three domains and are often found in con-junction with other *** these challenges,it is imperative to take proactive measures to prevent the further spread of *** includes the judicious and responsible use of antibiotics and efforts to mini-mize contact with animal ***‐specific strategies should be developed to effectively educate and engage relevant personnel in tackling this multifaceted *** efforts are vital to combat the dissem-ination of ESBL‐producing *** and preserve public health.

关键词： Escherichia coli Extended‐spectrumβ‐lactamases CTX‐M

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