Specific regulation of the senescence-associated secretory phenotype(SASP)is vital to block senescence-induced detrimental cellular plasticity.Recently,some chemical compounds called senomorphics have demonstrated suc...Specific regulation of the senescence-associated secretory phenotype(SASP)is vital to block senescence-induced detrimental cellular plasticity.Recently,some chemical compounds called senomorphics have demonstrated such potential,but it remains challenging to achieve site-specific activation and real-time monitoring of the action of senomorphics,posing great obstacles for transformable applications.Here,we report a tailor-made hydrogen sulfide(H_(2)S)donor(Lyso-FH_(2)S-Gal)as a new class of molecule senomorphics for spatially controlled delivery of H_(2)S for visualization of regulation of cellular senescence.It comprises four functional moieties in a single molecular structure,including a lysosome-targeting group for cell recognition,a lysosomal enzyme-cleaved scaffold for site-specific activation,thiocarbamate as the H_(2)S precursor,and a switchable fluorophore for concurrent selfreporting of H_(2)S release and senescence imaging.Lyso-FH_(2)S-Gal exhibited remarkable response selectivity,sustained H_(2)S release,and 141-fold fluorescence enhancement.In cellular models,Lyso-FH_(2) S-Gal preferentially enriched in senescent cells over nonsenescent cells,and alleviated the levels of SASP and reactive oxygen species(ROS)in senescent cells,while remaining inert in nonsenescent cells.More impressively,it efficiently inhibited the SASPmediated crosstalk between senescent cells and surrounding nonsenescent cells,thereby preventing senescence propagation.This work offers a useful molecular tool with the hope for controlled intervention of senescence-related important biological processes.展开更多
Kidney fibrosis is the final common pathway of virtually all chronic kidney disease(CKD).However,despite great progress in recent years,no targeted antifibrotic therapies have been approved.Epidemiologic,clinical,and ...Kidney fibrosis is the final common pathway of virtually all chronic kidney disease(CKD).However,despite great progress in recent years,no targeted antifibrotic therapies have been approved.Epidemiologic,clinical,and molecular evidence suggest that aging is a major contributor to the increasing incidence of CKD.Senescent renal tubular cells,fibroblasts,endothelial cells,and podocytes have been detected in the kidneys of patients with CKD and animal models.Nonetheless,although accumulated evidence supports the essential role of cellular senescence in CKD,the mechanisms that promote cell senescence and how senescent cells contribute to CKD remain largely unknown.In this review,we summarize the features of the cellular senescence of the kidney and discuss the possible functions of senescent cells in the pathogenesis of kidney fibrosis.We also address whether pharmacological approaches targeting senescent cells can be used to retard the the progression of kidney fibrosis.展开更多
Acute kidney injury(AKI)affects more than 20%of hospitalized patients and is a significant contributor to morbidity and mortality,primarily due to ischemia-reperfusion injury(IRI),which is one of the leading causes of...Acute kidney injury(AKI)affects more than 20%of hospitalized patients and is a significant contributor to morbidity and mortality,primarily due to ischemia-reperfusion injury(IRI),which is one of the leading causes of AKI.IRI not only exacerbates the immediate impact of AKI but also facilitates its progression to chronic kidney disease(CKD)and,in cases of preexisting CKD,to end-stage renal disease(ESRD).One of the critical pathological processes associated with IRI-AKI is cellular senescence,characterized by an irreversible arrest in the cell cycle,morphological and chromatin organization changes,altered transcriptional and metabolic profiles,and the development of a hypersecretory phenotype known as the senescence-associated secretory phenotype(SASP).The SASP amplifies senescence signals in surrounding normal cells through senescence-related pathways,contributing to tissue damage,fibrosis,and chronic inflammation.This review provides an overview of the defining features of senescent cells and explores the fundamental mechanisms underlying senescent cell generation following IRI.We elucidate the pivotal roles of cellular senescence in the transition from IRI-AKI to chronic kidney injury.Furthermore,we discuss emerging therapies targeting cellular senescence,including senolytics and senomorphics,which have shown promising results in both preclinical and clinical settings.These therapies position cellular senescence as a crucial target for the treatment of IRI in the kidneys.Additionally,advancements in single-cell sequencing technology and artificial intelligence-assisted drug screening are expected to accelerate the discovery of novel senescent biomarkers and synotherapeutics,paving the way for optimized and personalized therapeutic interventions.展开更多
Alzheimer’s disease(AD)is one of the most common neurodegenerative disorders,characterized by the accumulation of Aβand abnormal tau hyperphosphorylation.Despite substantial efforts in development of drugs targetin...Alzheimer’s disease(AD)is one of the most common neurodegenerative disorders,characterized by the accumulation of Aβand abnormal tau hyperphosphorylation.Despite substantial efforts in development of drugs targeting Aβand tau pathologies,effective therapeutic strategies for AD remain elusive.Recent attention has been paid to the significant role of cellular senescence in AD progression.Mounting evidence suggests that interventions targeting cellular senescence hold promise in improving cognitive function and ameliorating hallmark pathologies in AD.This narrative review provides a comprehensive summary and discussion of the physiological roles,characteristics,biomarkers,and commonly employed in vivo and in vitro models of cellular senescence,with a particular focus on various cell types in the brain,including astrocytes,microglia,oligodendrocyte precursor cells,neurons,and endothelial cells.The review further delves into factors influencing cellular senescence in AD and emphasizes the significance of targeting cellular senescence as a promising approach for AD treatment,which includes the utilization of senolytics and senomorphics.展开更多
基金supported by the National Natural Science Foundation of China(grant nos.NSFC22274044 and 21877031)the National Key Research and Development Program of China(grant no.2020YFA0210802)the Science and Technology Innovation Program of Hunan Province(grant no.2018RS3043).
文摘Specific regulation of the senescence-associated secretory phenotype(SASP)is vital to block senescence-induced detrimental cellular plasticity.Recently,some chemical compounds called senomorphics have demonstrated such potential,but it remains challenging to achieve site-specific activation and real-time monitoring of the action of senomorphics,posing great obstacles for transformable applications.Here,we report a tailor-made hydrogen sulfide(H_(2)S)donor(Lyso-FH_(2)S-Gal)as a new class of molecule senomorphics for spatially controlled delivery of H_(2)S for visualization of regulation of cellular senescence.It comprises four functional moieties in a single molecular structure,including a lysosome-targeting group for cell recognition,a lysosomal enzyme-cleaved scaffold for site-specific activation,thiocarbamate as the H_(2)S precursor,and a switchable fluorophore for concurrent selfreporting of H_(2)S release and senescence imaging.Lyso-FH_(2)S-Gal exhibited remarkable response selectivity,sustained H_(2)S release,and 141-fold fluorescence enhancement.In cellular models,Lyso-FH_(2) S-Gal preferentially enriched in senescent cells over nonsenescent cells,and alleviated the levels of SASP and reactive oxygen species(ROS)in senescent cells,while remaining inert in nonsenescent cells.More impressively,it efficiently inhibited the SASPmediated crosstalk between senescent cells and surrounding nonsenescent cells,thereby preventing senescence propagation.This work offers a useful molecular tool with the hope for controlled intervention of senescence-related important biological processes.
基金supported by grants from National High Level Hospital Clinical Research Funding(Scientific Research Fund of Peking University First Hospital,No.2023IR16State Key Laboratory of Vascular Homeostasis and Remodeling,Peking University,No.24QZ003)+2 种基金the National Natural Science Foundation of China(Nos.82090023 and 82330019)to Dr.Jing Niethe grants from Science/Technology Project of Sichuan Province(No.2024NSFSC1727)the 1.3.5 project for disciplines of excellence from West China Hospital of Sichuan University(No.ZYGD23015)to Dr.Ping Fu.
文摘Kidney fibrosis is the final common pathway of virtually all chronic kidney disease(CKD).However,despite great progress in recent years,no targeted antifibrotic therapies have been approved.Epidemiologic,clinical,and molecular evidence suggest that aging is a major contributor to the increasing incidence of CKD.Senescent renal tubular cells,fibroblasts,endothelial cells,and podocytes have been detected in the kidneys of patients with CKD and animal models.Nonetheless,although accumulated evidence supports the essential role of cellular senescence in CKD,the mechanisms that promote cell senescence and how senescent cells contribute to CKD remain largely unknown.In this review,we summarize the features of the cellular senescence of the kidney and discuss the possible functions of senescent cells in the pathogenesis of kidney fibrosis.We also address whether pharmacological approaches targeting senescent cells can be used to retard the the progression of kidney fibrosis.
基金This study was funded by the National Natural Science Foundation of China(Nos.82270709 and 82130021)the National Key R&D Program of China(Nos.2022YFC2502500 and 2022YFC2502502)+2 种基金the Michigan Medicine-PKUHSC Joint Institute for Translational and Clinical Research(No.BMU2022JI002)the Capital’s Funds for Health Improvement and Research(No.CFH2022-1-4071)the High Quality Clinical Research Project of Peking University First Hospital(No.2022CR83).
文摘Acute kidney injury(AKI)affects more than 20%of hospitalized patients and is a significant contributor to morbidity and mortality,primarily due to ischemia-reperfusion injury(IRI),which is one of the leading causes of AKI.IRI not only exacerbates the immediate impact of AKI but also facilitates its progression to chronic kidney disease(CKD)and,in cases of preexisting CKD,to end-stage renal disease(ESRD).One of the critical pathological processes associated with IRI-AKI is cellular senescence,characterized by an irreversible arrest in the cell cycle,morphological and chromatin organization changes,altered transcriptional and metabolic profiles,and the development of a hypersecretory phenotype known as the senescence-associated secretory phenotype(SASP).The SASP amplifies senescence signals in surrounding normal cells through senescence-related pathways,contributing to tissue damage,fibrosis,and chronic inflammation.This review provides an overview of the defining features of senescent cells and explores the fundamental mechanisms underlying senescent cell generation following IRI.We elucidate the pivotal roles of cellular senescence in the transition from IRI-AKI to chronic kidney injury.Furthermore,we discuss emerging therapies targeting cellular senescence,including senolytics and senomorphics,which have shown promising results in both preclinical and clinical settings.These therapies position cellular senescence as a crucial target for the treatment of IRI in the kidneys.Additionally,advancements in single-cell sequencing technology and artificial intelligence-assisted drug screening are expected to accelerate the discovery of novel senescent biomarkers and synotherapeutics,paving the way for optimized and personalized therapeutic interventions.
基金supported by the National Natural Science Foundation of China(32300959 and 32100918)the China Postdoctoral Science Foundation(2021M690060 and 2022T150227)+1 种基金Guangzhou Scientific Research Grant(SL2024A04J00578)the SCNU Young Faculty Development Program(22KJ04).
文摘Alzheimer’s disease(AD)is one of the most common neurodegenerative disorders,characterized by the accumulation of Aβand abnormal tau hyperphosphorylation.Despite substantial efforts in development of drugs targeting Aβand tau pathologies,effective therapeutic strategies for AD remain elusive.Recent attention has been paid to the significant role of cellular senescence in AD progression.Mounting evidence suggests that interventions targeting cellular senescence hold promise in improving cognitive function and ameliorating hallmark pathologies in AD.This narrative review provides a comprehensive summary and discussion of the physiological roles,characteristics,biomarkers,and commonly employed in vivo and in vitro models of cellular senescence,with a particular focus on various cell types in the brain,including astrocytes,microglia,oligodendrocyte precursor cells,neurons,and endothelial cells.The review further delves into factors influencing cellular senescence in AD and emphasizes the significance of targeting cellular senescence as a promising approach for AD treatment,which includes the utilization of senolytics and senomorphics.
