Cellular senescence is a signal transduction process which maintained genomic stability and stopped mammalian cell growth. Furthermore, cellular senescence induces a protective response to a variety of DNA damage. How...Cellular senescence is a signal transduction process which maintained genomic stability and stopped mammalian cell growth. Furthermore, cellular senescence induces a protective response to a variety of DNA damage. However, this process is also associated with apoptosis, upregulated secretion of inflammatory cytokine, and promoted surrounding tissue damage. When cellular senescence accumulates to a certain extent, it triggers geriatric diseases, such as chronic inflammation, immune senescence-associated tumors and incontrollable infections. Cellular senescence gene SENEX, which was cloned in 2004, has been demonstrated to play a unique gatekeeper function in human endothelial cells when stress-induced pre-mature senescence and apoptosis occurr. The phenomenon that CD4+CD25+ Treg cells accumulated in the aged population has been well studied in recent years. Now Treg accumulation related to immune-pathology has attracted more interest. CD4+CD25+ Treg did not decline and age, but accumulated and suppressed immunoreaction. The enhanced Treg number and function may be associated with stress-induced premature senescence-mediated unique cellular senescence protection mechanisms, and SENEX may play a critical role in this process. In this article, we summarize the cellular senescence and SENEX gene in the accumulation and functional activity of CD4+CD25+ Treg in the elderly.展开更多
Objective:Organoids are a powerful tool with broad application prospects in biomedicine.Notably,they provide alternatives to animal models for testing potential drugs before clinical trials.However,the number of passa...Objective:Organoids are a powerful tool with broad application prospects in biomedicine.Notably,they provide alternatives to animal models for testing potential drugs before clinical trials.However,the number of passages for which organoids maintain cellular vitality ex vivo remains unclear.Methods:Herein,we constructed 55 gastric organoids from 35 individuals,serially passaged the organoids,and captured microscopic images for phenotypic evaluation.Senescence-associatedβ-galactosidase(SA-β-Gal),cell diameter in suspension,and gene expression reflecting cell cycle regulation were examined.The YOLOv3 object detection algorithm integrated with a convolutional block attention module(CBAM)was used to evaluate organoid vitality.Results:SA-β-Gal staining intensity;single-cell diameter;and expression of p15,p16,p21,CCNA2,CCNE2,and LMNB1 reflected the progression of aging in organoids during passaging.The CBAM-YOLOv3 algorithm precisely evaluated aging organoids on the basis of organoid average diameter,organoid number,and number×diameter,and the findings positively correlated with SA-β-Gal staining and single-cell diameter.Organoids derived from normal gastric mucosa had limited passaging ability(passages 1–5),before aging,whereas tumor organoids showed unlimited passaging potential for more than 45 passages(511 days)without showing clear senescence.Conclusions:Given the lack of indicators for evaluating organoid growth status,we established a reliable approach for integrated analysis of phenotypic parameters that uses an artificial intelligence algorithm to indicate organoid vitality.This method enables precise evaluation of organoid status in biomedical studies and monitoring of living biobanks.展开更多
BACKGROUND Cellular senescence,a state of stable growth arrest,is intertwined with human cancers.However,characterization of cellular senescence-associated phenotypes in hepatocellular carcinoma(HCC)remains unexplored...BACKGROUND Cellular senescence,a state of stable growth arrest,is intertwined with human cancers.However,characterization of cellular senescence-associated phenotypes in hepatocellular carcinoma(HCC)remains unexplored.AIM To address this issue,we delineated cellular senescence landscape across HCC.METHODS We enrolled two HCC datasets,TCGA-LIHC and International Cancer Genome Consortium(ICGC).Unsupervised clustering was executed to probe tumor heterogeneity based upon cellular senescence genes.Least absolute shrinkage and selection operator algorithm were utilized to define a cellular senescence-relevant scoring system.TRNP1 expression was measured in HCCs and normal tissues through immunohistochemistry,immunoblotting and quantitative real-time polymerase chain reaction.The influence of TMF-regulated nuclear protein(TRNP)1 on HCC senescence and growth was proven via a series of experiments.RESULTS TCGA-LIHC patients were classified as three cellular senescence subtypes,named C1–3.The robustness and reproducibility of these subtypes were proven in the ICGC cohort.C2 had the worst overall survival,C1 the next,and C3 the best.C2 presented the highest levels of immune checkpoints,abundance of immune cells,and immunogenetic indicators.Thus,C2 might possibly respond to immunotherapy.C2 had the lowest somatic mutation rate,while C1 presented the highest copy number variations.A cellular senescence-relevant gene signature was generated,which can predict patient survival,and chemo-or immunotherapeutic response.Experimentally,it was proven that TRNP1 presented the remarkable upregulation in HCCs.TRNP1 knockdown induced apoptosis and senescence of HCC cells and attenuated tumor growth.CONCLUSION These findings provide a systematic framework for assessing cellular senescence in HCC,which decode the tumor heterogeneity and tailor the pharmacological interventions to improve clinical management.展开更多
Tissue homeostasis requires a carefully-orchestrated balance between cell proliferation, cellular senescence and cell death. Cells proliferate through a cell cycle that is tightly regulated by cyclin-dependent kinase ...Tissue homeostasis requires a carefully-orchestrated balance between cell proliferation, cellular senescence and cell death. Cells proliferate through a cell cycle that is tightly regulated by cyclin-dependent kinase activities. Cellular senescence is a safeguard program limiting the proliferative competence of cells in living organisms. Apoptosis eliminates unwanted cells by the coordinated activity of gene products that regulate and effect cell death. The intimate link between the cell cycle, cellular senes- cence, apoptosis regulation, cancer development and tumor responses to cancer treatment has become eminently apparent. Extensive research on tumor suppressor genes, oncogenes, the cell cycle and apoptosis regulatory genes has revealed how the DNA damage-sensing and -signaling pathways, referred to as the DNA-damage response network, are tied to cell proliferation, cell-cycle arrest, cellular senescence and apoptosis. DNA-damage responses are complex, involving “sensor” proteins that sense the damage, and transmit signals to “transducer” proteins, which, in turn, convey the signals to numerous “effector” proteins implicated in specific cellular pathways, including DNA repair mechanisms, cell-cycle checkpoints, cellular senescence and apoptosis. The Bcl-2 family of proteins stands among the most crucial regulators of apoptosis and performs vital functions in deciding whether a cell will live or die after cancer chemotherapy and irradiation. In addition, several studies have now revealed that members of the Bcl-2 family also interface with the cell cycle, DNA repair/recombination and cellular senescence, effects that are generally distinct from their function in apoptosis. In this review, we report progress in understanding the molecular networks that regulate cell-cycle checkpoints, cellular senescence and apoptosis after DNA damage, and discuss the influence of some Bcl-2 family members on cell-cycle checkpoint regulation.展开更多
Cellular senescence and proliferation are essential for wound healing and tissue remodeling.However,senescence-proliferation cell fate after peripheral nerve injury has not been clearly revealed.Here,post-injury gene ...Cellular senescence and proliferation are essential for wound healing and tissue remodeling.However,senescence-proliferation cell fate after peripheral nerve injury has not been clearly revealed.Here,post-injury gene expression patterns in rat sciatic nerve stumps(SRP113121)and L4–5 dorsal root ganglia(SRP200823)obtained from the National Center for Biotechnology Information were analyzed to decipher cellular senescence and proliferation-associated genetic changes.We first constructed a rat sciatic nerve crush model.Then,β-galactosidase activities were determined to indicate the existence of cellular senescence in the injured sciatic nerve.Ki67 and EdU immunostaining was performed to indicate cellular proliferation in the injured sciatic nerve.Both cellular senescence and proliferation were less vigorous in the dorsal root ganglia than in sciatic nerve stumps.These results reveal the dynamic changes of injury-induced cellular senescence and proliferation from both genetic and morphological aspects,and thus extend our understanding of the biological processes following peripheral nerve injury.The study was approved by the Animal Ethics Committee of Nantong University,China(approval No.20190226-001)on February 26,2019.展开更多
Immunoglobulin G4-related sialadenitis(IgG4-RS)is an immune-mediated fibro-inflammatory disease and the pathogenesis is still not fully understood.The aim of this study was to explore the role and mechanism of interle...Immunoglobulin G4-related sialadenitis(IgG4-RS)is an immune-mediated fibro-inflammatory disease and the pathogenesis is still not fully understood.The aim of this study was to explore the role and mechanism of interleukin-13(IL-13)in the cellular senescence during the progress of IgG4-RS.We found that the expression of IL-13 and IL-13 receptorα1(IL-13Rα1)as well as the number of senescent cells were significantly higher in the submandibular glands(SMGs)of IgG4-RS patients.IL-13 directly induced senescence as shown by the elevated activity of senescence-associatedβ-galactosidase(SA-β-gal),the decreased cell proliferation,and the upregulation of senescence markers(p53 and p16)and senescence-associated secretory phenotype(SASP)factors(IL-1βand IL-6)in SMG-C6 cells.Mechanistically,IL-13 increased the level of phosphorylated signal transducer and activator of transcription 6(p-STAT6)and mitochondrial-reactive oxygen species(mt ROS),while decreased the mitochondrial membrane potential,ATP level,and the expression and activity of superoxide dismutase 2(SOD2).Notably,the IL-13-induced cellular senescence and mitochondrial dysfunction could be inhibited by pretreatment with either STAT6 inhibitor AS1517499 or mitochondria-targeted ROS scavenger Mito TEMPO.Moreover,IL-13 increased the interaction between p-STAT6 and c AMP-response element binding protein(CREB)-binding protein(CBP)and decreased the transcriptional activity of CREB on SOD2.Taken together,our findings revealed a critical role of IL-13 in the induction of salivary gland epithelial cell senescence through the elevated mitochondrial oxidative stress in a STAT6–CREB–SOD2-dependent pathway in IgG4-RS.展开更多
Pathological retinal neovascularization is the hallmark of primary blinding diseases across all age groups,yet surprisingly little is known about the causative factors.These diseases include diabetic retinopathy and r...Pathological retinal neovascularization is the hallmark of primary blinding diseases across all age groups,yet surprisingly little is known about the causative factors.These diseases include diabetic retinopathy and retinopathy of prematurity where progressive decay of retinal vasculature yields zones of neural ischemia.These avascular zones and the hypoxic neurons and glia that reside in them are the source of pro-angiogenic factors that mediate destructive pre-retinal angiogenesis.Central neurons such as retinal ganglion cells(RGCs),which are directly apposed to degenerating vasculature in ischemic retinopathies,require stable metabolic supply for proper function.However,we unexpectedly found that RGCs are resilient to hypoxia/ischemia and a generally compromised metabolic supply and instead of degenerating,trigger protective mechanisms of cellular senescence.Paradoxically,while potentially favoring neuronal survival,the senescent state of RGCs is incompatible with vascular repair as they adopt a senescence-associated secretory phenotype(SASP)that provokes release of a secretome of inflammatory cytokines that drives paracrine senescence and further exacerbates pathological angiogenesis.The mechanisms that lead to retinal cellular senescence and dormancy as well as the therapeutic potential of targeting these pathways will be discussed.展开更多
Osteosarcoma is the most common primary malignancy of bones and primarily occurs in adolescents and young adults.However,a second smaller peak of osteosarcoma incidence was reported in the elderly aged more than 60.El...Osteosarcoma is the most common primary malignancy of bones and primarily occurs in adolescents and young adults.However,a second smaller peak of osteosarcoma incidence was reported in the elderly aged more than 60.Elderly patients with osteosarcoma exhibit different characteristics compared to young patients,which usually results in a poor prognosis.The mechanism underlying osteosarcoma development in elderly patients is intriguing and of significant value in clinical applications.Senescent cells can accelerate tumor progression by metabolic reprogramming.Recent research has shown that methylmalonic acid(MMA)was significantly up-regulated in the serum of older individuals and played a central role in the development of aggressive characteristics.We found that the significant accumulation of MMA in elderly patients imparted proliferative potential to osteosarcoma cells.The expression of MAFB was excessively up-regulated in osteosarcoma specimens and was further enhanced in response to MMA accumulation as the patient aged.Specifically,we first confirmed a novel molecular mechanism between cellular senescence and cancer,in which the MMA-driven transcriptional reprogramming of the MAFB-NOTCH3 axis accelerated osteosarcoma progression via the activation of PI3K-AKT pathways.Moreover,the down-regulation of the MAFB-NOTCH3 axis increased the sensitivity and effect of AKT inhibitors in osteosarcoma through significant inhibition of AKT phosphorylation.In conclusion,we confirmed that MAFB is a novel age-dependent biomarker for osteosarcoma,and targeting the MAFB-NOTCH3 axis in combination with AKT inhibition can serve as a novel therapeutic strategy for elderly patients with osteosarcoma in experimental and clinical trials.展开更多
Cellular senescence has emerged as an important contributor to aging and age-related diseases.Non-ionizing radiation(NIR),including ultraviolet radiation and electromagnetic fields,has been increasingly recognized as ...Cellular senescence has emerged as an important contributor to aging and age-related diseases.Non-ionizing radiation(NIR),including ultraviolet radiation and electromagnetic fields,has been increasingly recognized as a key inducer of premature senescence.In this review,we discuss the molecular mechanisms of NIR-induced cellular senescence and its effects on aging and age-related diseases.We also summarize the modulation strategies for NIR-induced cellular senescence.A better understanding of the complex relationship between nonionizing radiation,cellular senescence and age-related pathology may lead to interventions to ameliorate radiation damage and delay aging.Further research is still needed to elucidate the precise mechanisms,dose-response effects,and to develop protective strategies against radiation-induced senescence.展开更多
Idiopathic pulmonary fibrosis(IPF)is a progressive fibrosing interstitial lung disease with high morbidity and mortality but unclear etiology and incomplete pathophysiological understandings,making the discovery of ef...Idiopathic pulmonary fibrosis(IPF)is a progressive fibrosing interstitial lung disease with high morbidity and mortality but unclear etiology and incomplete pathophysiological understandings,making the discovery of effective therapeutics arduous.Currently,two drugs,nintedanib and pirfenidone,are available for IPF treatment which can slow down the fibrotic scarring in the lung but are unable to provide disease resolution.Hence,further revelation of the molecular mechanisms of IPF is critical for the development of novel therapeutics.Isthmin-1(ISM1)is a secreted anti-inflammatory protein highly expressed in the mouse and human lung.Ism1^(-/-)mice presented spontaneous and progressive lung emphysema,as well as heightened acute lung injury(ALI)upon lipopolysaccharide(LPS)treatment with an accompanied increase of post-LPS-ALI pulmonary fibrosis.ISM1 is important for lung homeostasis with airway-delivered recombinant ISM1(rISM1)suppressing cigarette smoke-induced emphysema,LPS-ALI,and house-dust mites(HDM)-induced asthma-like symptoms in mice.However,the role of ISM1 in pulmonary fibrosis is yet to be clearly understood.In this work,we show that Ism1^(-/-)mice presented heightened bleomycin-induced pulmonary fibrosis(BIPF),with enhanced immune cell infiltration,myofibroblast accumulation,and collagen deposition.ISM1 deficiency also led to increased cellular senescence in mouse lungs,isolated primary alveolar type II epithelial cells,and primary lung fibroblasts upon bleomycin treatment.Ism1^(-/-)mice also showed delayed resolution of pulmonary fibrosis with reduced lipofibroblasts and downregulation of lipid synthesis-related genes.These results are in congruence with the RNA-seq data which demonstrated gene expression alterations in Ism1^(-/-)lung that are linked to predisposition to pulmonary fibrosis and dysregulation of lipid metabolism pathways.Gene expression analyses showed that Ism1 is similarly dysregulated in the lungs of BIPF and human IPF patients.These findings reveal an anti-fibrotic role of ISM1 in mouse lungs and provide the foundation to further investigate possible therapeutic applications of ISM1 for pulmonary fibrosis in the future.展开更多
Hand-foot syndrome(HFS)is a widely recognized dose-limiting cutaneous toxicity effect of fluoropyrimidine chemotherapy agents that impairs clinical benefits and treatment outcomes.Even though the cause and pathophysio...Hand-foot syndrome(HFS)is a widely recognized dose-limiting cutaneous toxicity effect of fluoropyrimidine chemotherapy agents that impairs clinical benefits and treatment outcomes.Even though the cause and pathophysiology of HFS are relatively widely reported,how the toxicity of fluoropyrimidine translates into persistent inflammation has not been studied.Additionally,prevention and treatment strategies for HFS based on its mechanistic occurrence and development are scarce.In our study,we demonstrated that cGAS-STING signaling pathway-mediated cellular senescence played a critical role in the inflammatory reaction and provided a therapeutic solution for HFS.Mechanistically,DNA damage,as the primary cytotoxic cause,in keratinocytes induces cell cycle arrest,activates the cGAS-STING signaling pathway,and subsequently mediates cellular senescence,ultimately fueling a robust secondary inflammatory response that results in HFS.More importantly,the thymidine prodrug thymidine diacetate was proven to be effective in preventing HFS by compensating for thymidylate deficiency to facilitate the replication and repair of DNA and thus causing the escape from cellular senescence.These data highlight the importance of DNA damage-mediated cellular senescence in the etiology of HFS and provide a potential therapeutic anchor point for fluoropyrimidine-induced HFS.展开更多
Background:Radiation ulcers are a common and severe injury after uncontrolled exposure to ionizing radiation.The most important feature of radiation ulcers is progressive ulceration,which results in the expansion of r...Background:Radiation ulcers are a common and severe injury after uncontrolled exposure to ionizing radiation.The most important feature of radiation ulcers is progressive ulceration,which results in the expansion of radiation injury to the nonirradiated area and refractory wounds.Current theories cannot explain the progression of radiation ulcers.Cellular senescence refers to as irre-versible growth arrest that occurs after exposure to stress,which contributes to tissue dysfunction by inducing paracrine senescence,stem cell dysfunction and chronic inflammation.However,it is not yet clear how cellular senescence facilitates the continuous progression of radiation ulcers.Here,we aim to investigate the role of cellular senescence in promoting progressive radiation ulcers and indicate a potential therapeutic strategy for radiation ulcers.Methods:Radiation ulcer animal models were established by local exposure to 40 Gy X-ray radiation and continuously evaluated for>260 days.The roles of cellular senescence in the progression of radiation ulcers were assessed using pathological analysis,molecular detection and RNA sequencing.Then,the therapeutic effects of conditioned medium from human umbilical cord mesenchymal stem cells(uMSC-CM)were investigated in radiation ulcer models.Results:Radiation ulcer animal models with features of clinical patients were established to investigate the primary mechanisms responsible for the progression of radiation ulcers.We have characterized cellular senescence as being closely associated with the progression of radiation ulcers and found that exogenous transplantation of senescent cells significantly aggravated them.Mechanistic studies and RNA sequencing suggested that radiation-induced senescent cell secretions were responsible for facilitating paracrine senescence and promoting the progression of radiation ulcers.Finally,we found that uMSC-CM was effective in mitigating the progression of radiation ulcers by inhibiting cellular senescence.Conclusions:Our findings not only characterize the roles of cellular senescence in the progression of radiation ulcers but also indicate the therapeutic potential of senescent cells in their treatment.展开更多
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
Echinacoside is one of the phenylethanoids isolated from the stems of Cistanches salsa. Our previous research showed that echinacoside has anti-senescence activity. To investigate the mechanism of echinacoside＇s anti...Echinacoside is one of the phenylethanoids isolated from the stems of Cistanches salsa. Our previous research showed that echinacoside has anti-senescence activity. To investigate the mechanism of echinacoside＇s anti-senescence activity, the expressions of p53, p21, p16 and Rb at the mRNA and protein levels were determined. Results showed that the expression of p53 was down-regulated significantly in a dose dependent manner after treatment with echinacoside. Further experiments suggested that the down-regulation of p53 may be correlated with the upregulation of SIRT1. In addition, echinacoside may exhibit considerable higher affinity towards SIRT1 than resveratrol, according to our molecular docking simulation. In conclusion, we expect that echinacoside might be a promising candidate for regulating cell senescence.展开更多
Cellular senescence is an irreversible cell cycle arrest program in response to various exogenous and endogenous stimuli like telomere dysfunction and DNA damage.It has been widely accepted as an antitumor program and...Cellular senescence is an irreversible cell cycle arrest program in response to various exogenous and endogenous stimuli like telomere dysfunction and DNA damage.It has been widely accepted as an antitumor program and is also found closely related to embryo development,tissue repair,organismal aging and age-related degenerative diseases.In the past decades,numerous efforts have been made to uncover the gene regulatory mechanisms of cellular senescence.There is a strong demand to integrate these data from various resources into one open platform.To facilitate researchers on cellular senescence,we have developed Human Cellular Senescence Gene Database（HCSGD） by integrating multiple online published data sources into a comprehensive senescence gene annotation platform（http：//bioinfo.au.tsinghua.edu.cn/member/xwwang/HCSGD）.Potential Human Cellular Senescence Genes（HCSGS）were collected by combining information from published literatures,gene expression profiling data and Protein-Protein Interaction networks.Additionally,genes are annotated with gene ontology annotation and microRNA/drug/compound target information.HCSGD provides a valuable resource to visualize cellular senescence gene networks,browse annotated functional information,and retrieve senescenceassociated genes with a user-friendly web interface.展开更多
Background Cellular senescence,an irreversible state of cell-cycle arrest triggered by multiple stress factors,plays a key role in organ development and wound healing.Accumulated senescent cells also promote tissue in...Background Cellular senescence,an irreversible state of cell-cycle arrest triggered by multiple stress factors,plays a key role in organ development and wound healing.Accumulated senescent cells also promote tissue inflammation and involve in various diseases including myocardial infarction,atherosclerosis,diabetes and nonalcoholic steatohepatitis.Understanding the mechanism and consequences of cellular senescence is crucial to develop new therapies for diseases.Here,we describe the characteristics of senescent cells and involvement of senescent cardiac cells in heart development,regeneration and diseases.We summarize the work in this area and provide directions and clues for future studies.展开更多
Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescen...Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescence in vitro and increases longevity in vivo,but has poor water solubility and limited bioavailability.In this study,a food-grade and senescent cell-targeted delivery system for fisetin was developed based on whey protein isolate-galactooligosaccharides(WPI-GOS)Maillard conjugate,which could recognize senescence associatedβ-galactosidase in senescent cells.The fisetin nanoparticles possessed a high encapsulation efficiency,excellent dispersibility in water,good storage stability and well biocompatibility.Moreover,they could effectively accumulate and retain in senescent cells with excellent senescent cell-targeting efficacy,and inhibit the oxidative stress-induced cellular senescence in vitro.Thus,this novel nanoparticle system based on WPI-GOS Maillard conjugate showed promise to deliver hydrophobic bioactive ingredients like fisetin to senescent cells to improve their bioavailability and anti-senescence effect.展开更多
Summary： Senescence is an important obstacle to cancer development. Engaging a senescent response may be an effective way to cure acute myeloid leukemia （AML）. The aim of this study was to examine the effect of res...Summary： Senescence is an important obstacle to cancer development. Engaging a senescent response may be an effective way to cure acute myeloid leukemia （AML）. The aim of this study was to examine the effect of resveratrol-downregulated phosphorylated liver kinase B1 （pLKB1） on the senescence of acute myeloid leukemia （AML） stem cells. The protein expressions of pLKB 1 and Sirtuin 1 （SIRT1）, a regulator ofpLKB1, were measured in CD34＋CD38-KGla cells treated with resveratrol （40 μmol/L） or not by Western blotting. Senescence-related factors were examined, including p21 mRNA tested by real-time PCR, cell morphology by senescence-associated β-galactosidase （SA-β-gal） staining, cell pro- liferation by MTT assay and cell cycle by flow cytometry. Besides, apoptosis was flow cytometrically determined. The results showed that pLKB1 was highly expressed in CD34＋CD38- KGla cells, and resveratrol, which could downregulate pLKB1 through activation of SIRT1, induced senescence and apoptosis of CD34＋CD38- KGla cells. It was concluded that resveratrol-downregulated pLKB1 is in- volved in the senescence of AML stem cells.展开更多
The intrinsic oncogenic mechanisms and properties of the tumor microenvironment(TME)have been extensively investigated.Primary features of the TME include metabolic reprogramming,hypoxia,chronic inflammation,and tumor...The intrinsic oncogenic mechanisms and properties of the tumor microenvironment(TME)have been extensively investigated.Primary features of the TME include metabolic reprogramming,hypoxia,chronic inflammation,and tumor immunosuppression.Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME.Specifically,hypoxic adaptation,metabolic dysregulation,and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation,thereby promoting the progression of tumor events.This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME,with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells.The available findings suggest that components of the TME collectively contribute to the progression of tumor events.The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.展开更多
Skin Exposure of skin to ionizing radiation can induce acute or chronic biological effects,resulting in radiation-induced skin injury(RSI).Premature cellular senescence,caused by oxidative stress and/or DNA damage fro...Skin Exposure of skin to ionizing radiation can induce acute or chronic biological effects,resulting in radiation-induced skin injury(RSI).Premature cellular senescence,caused by oxidative stress and/or DNA damage from chemical or physical agents,leads to the decrease of cellular proliferation and physiological function.Persistent DNA damage and accumulation of senescent cells are associated with the progression of radiation-induced injury.Atopic dermatitis and RSI have similar inflammatory symptoms.The treatment of tacrolimus(TAC)in atopic dermatitis may be associated with premature cellular senescence.TAC can prevent the onset of cellular senes-cence by inactivating the p38 mitogen-activated protein kinase(p38 MAPK).The activation of p38 MAPK can induce the senescence-associated secretory phenotype(SASP)by enhancing the transcriptional activity of nuclear factor kappa-B(NF-κB),which ultimately leads to premature cellular senescence.FK506 binding protein 51(FKBP51)exhibits resistance to ionizing radiation,but the mechanism of TAC regulation of ionizing radiation-induced premature senescence still needs further study.This review discusses the mechanism of cellular senes-cence in RSI and the role of TAC in both dermatitis and RSI.展开更多
文摘Cellular senescence is a signal transduction process which maintained genomic stability and stopped mammalian cell growth. Furthermore, cellular senescence induces a protective response to a variety of DNA damage. However, this process is also associated with apoptosis, upregulated secretion of inflammatory cytokine, and promoted surrounding tissue damage. When cellular senescence accumulates to a certain extent, it triggers geriatric diseases, such as chronic inflammation, immune senescence-associated tumors and incontrollable infections. Cellular senescence gene SENEX, which was cloned in 2004, has been demonstrated to play a unique gatekeeper function in human endothelial cells when stress-induced pre-mature senescence and apoptosis occurr. The phenomenon that CD4+CD25+ Treg cells accumulated in the aged population has been well studied in recent years. Now Treg accumulation related to immune-pathology has attracted more interest. CD4+CD25+ Treg did not decline and age, but accumulated and suppressed immunoreaction. The enhanced Treg number and function may be associated with stress-induced premature senescence-mediated unique cellular senescence protection mechanisms, and SENEX may play a critical role in this process. In this article, we summarize the cellular senescence and SENEX gene in the accumulation and functional activity of CD4+CD25+ Treg in the elderly.
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.82072602 and 82173222)the Science and Technology Commission of Shanghai Municipality(Grant Nos.20DZ2201900 and 18411953100)+1 种基金the Innovation Foundation of Translational Medicine of Shanghai Jiaotong University School of Medicine(Grant No.TM202001)the Collaborative Innovation Center for Clinical and Translational Science of the Chinese Ministry of Education&Shanghai(Grant No.CCTS-2022202)。
文摘Objective:Organoids are a powerful tool with broad application prospects in biomedicine.Notably,they provide alternatives to animal models for testing potential drugs before clinical trials.However,the number of passages for which organoids maintain cellular vitality ex vivo remains unclear.Methods:Herein,we constructed 55 gastric organoids from 35 individuals,serially passaged the organoids,and captured microscopic images for phenotypic evaluation.Senescence-associatedβ-galactosidase(SA-β-Gal),cell diameter in suspension,and gene expression reflecting cell cycle regulation were examined.The YOLOv3 object detection algorithm integrated with a convolutional block attention module(CBAM)was used to evaluate organoid vitality.Results:SA-β-Gal staining intensity;single-cell diameter;and expression of p15,p16,p21,CCNA2,CCNE2,and LMNB1 reflected the progression of aging in organoids during passaging.The CBAM-YOLOv3 algorithm precisely evaluated aging organoids on the basis of organoid average diameter,organoid number,and number×diameter,and the findings positively correlated with SA-β-Gal staining and single-cell diameter.Organoids derived from normal gastric mucosa had limited passaging ability(passages 1–5),before aging,whereas tumor organoids showed unlimited passaging potential for more than 45 passages(511 days)without showing clear senescence.Conclusions:Given the lack of indicators for evaluating organoid growth status,we established a reliable approach for integrated analysis of phenotypic parameters that uses an artificial intelligence algorithm to indicate organoid vitality.This method enables precise evaluation of organoid status in biomedical studies and monitoring of living biobanks.
文摘BACKGROUND Cellular senescence,a state of stable growth arrest,is intertwined with human cancers.However,characterization of cellular senescence-associated phenotypes in hepatocellular carcinoma(HCC)remains unexplored.AIM To address this issue,we delineated cellular senescence landscape across HCC.METHODS We enrolled two HCC datasets,TCGA-LIHC and International Cancer Genome Consortium(ICGC).Unsupervised clustering was executed to probe tumor heterogeneity based upon cellular senescence genes.Least absolute shrinkage and selection operator algorithm were utilized to define a cellular senescence-relevant scoring system.TRNP1 expression was measured in HCCs and normal tissues through immunohistochemistry,immunoblotting and quantitative real-time polymerase chain reaction.The influence of TMF-regulated nuclear protein(TRNP)1 on HCC senescence and growth was proven via a series of experiments.RESULTS TCGA-LIHC patients were classified as three cellular senescence subtypes,named C1–3.The robustness and reproducibility of these subtypes were proven in the ICGC cohort.C2 had the worst overall survival,C1 the next,and C3 the best.C2 presented the highest levels of immune checkpoints,abundance of immune cells,and immunogenetic indicators.Thus,C2 might possibly respond to immunotherapy.C2 had the lowest somatic mutation rate,while C1 presented the highest copy number variations.A cellular senescence-relevant gene signature was generated,which can predict patient survival,and chemo-or immunotherapeutic response.Experimentally,it was proven that TRNP1 presented the remarkable upregulation in HCCs.TRNP1 knockdown induced apoptosis and senescence of HCC cells and attenuated tumor growth.CONCLUSION These findings provide a systematic framework for assessing cellular senescence in HCC,which decode the tumor heterogeneity and tailor the pharmacological interventions to improve clinical management.
基金the Canadian Institutes of Health Research and the Cancer Research Society, and fellowships by the Health Research Funds of Quebec, Canada
文摘Tissue homeostasis requires a carefully-orchestrated balance between cell proliferation, cellular senescence and cell death. Cells proliferate through a cell cycle that is tightly regulated by cyclin-dependent kinase activities. Cellular senescence is a safeguard program limiting the proliferative competence of cells in living organisms. Apoptosis eliminates unwanted cells by the coordinated activity of gene products that regulate and effect cell death. The intimate link between the cell cycle, cellular senes- cence, apoptosis regulation, cancer development and tumor responses to cancer treatment has become eminently apparent. Extensive research on tumor suppressor genes, oncogenes, the cell cycle and apoptosis regulatory genes has revealed how the DNA damage-sensing and -signaling pathways, referred to as the DNA-damage response network, are tied to cell proliferation, cell-cycle arrest, cellular senescence and apoptosis. DNA-damage responses are complex, involving “sensor” proteins that sense the damage, and transmit signals to “transducer” proteins, which, in turn, convey the signals to numerous “effector” proteins implicated in specific cellular pathways, including DNA repair mechanisms, cell-cycle checkpoints, cellular senescence and apoptosis. The Bcl-2 family of proteins stands among the most crucial regulators of apoptosis and performs vital functions in deciding whether a cell will live or die after cancer chemotherapy and irradiation. In addition, several studies have now revealed that members of the Bcl-2 family also interface with the cell cycle, DNA repair/recombination and cellular senescence, effects that are generally distinct from their function in apoptosis. In this review, we report progress in understanding the molecular networks that regulate cell-cycle checkpoints, cellular senescence and apoptosis after DNA damage, and discuss the influence of some Bcl-2 family members on cell-cycle checkpoint regulation.
基金supported by the National Natural Science Foundation of China,No.31970968(to SYL)Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)。
文摘Cellular senescence and proliferation are essential for wound healing and tissue remodeling.However,senescence-proliferation cell fate after peripheral nerve injury has not been clearly revealed.Here,post-injury gene expression patterns in rat sciatic nerve stumps(SRP113121)and L4–5 dorsal root ganglia(SRP200823)obtained from the National Center for Biotechnology Information were analyzed to decipher cellular senescence and proliferation-associated genetic changes.We first constructed a rat sciatic nerve crush model.Then,β-galactosidase activities were determined to indicate the existence of cellular senescence in the injured sciatic nerve.Ki67 and EdU immunostaining was performed to indicate cellular proliferation in the injured sciatic nerve.Both cellular senescence and proliferation were less vigorous in the dorsal root ganglia than in sciatic nerve stumps.These results reveal the dynamic changes of injury-induced cellular senescence and proliferation from both genetic and morphological aspects,and thus extend our understanding of the biological processes following peripheral nerve injury.The study was approved by the Animal Ethics Committee of Nantong University,China(approval No.20190226-001)on February 26,2019.
基金supported by the National Natural Science Foundation of China(Nos.81974151,31972908,81991500,and 81991502)。
文摘Immunoglobulin G4-related sialadenitis(IgG4-RS)is an immune-mediated fibro-inflammatory disease and the pathogenesis is still not fully understood.The aim of this study was to explore the role and mechanism of interleukin-13(IL-13)in the cellular senescence during the progress of IgG4-RS.We found that the expression of IL-13 and IL-13 receptorα1(IL-13Rα1)as well as the number of senescent cells were significantly higher in the submandibular glands(SMGs)of IgG4-RS patients.IL-13 directly induced senescence as shown by the elevated activity of senescence-associatedβ-galactosidase(SA-β-gal),the decreased cell proliferation,and the upregulation of senescence markers(p53 and p16)and senescence-associated secretory phenotype(SASP)factors(IL-1βand IL-6)in SMG-C6 cells.Mechanistically,IL-13 increased the level of phosphorylated signal transducer and activator of transcription 6(p-STAT6)and mitochondrial-reactive oxygen species(mt ROS),while decreased the mitochondrial membrane potential,ATP level,and the expression and activity of superoxide dismutase 2(SOD2).Notably,the IL-13-induced cellular senescence and mitochondrial dysfunction could be inhibited by pretreatment with either STAT6 inhibitor AS1517499 or mitochondria-targeted ROS scavenger Mito TEMPO.Moreover,IL-13 increased the interaction between p-STAT6 and c AMP-response element binding protein(CREB)-binding protein(CBP)and decreased the transcriptional activity of CREB on SOD2.Taken together,our findings revealed a critical role of IL-13 in the induction of salivary gland epithelial cell senescence through the elevated mitochondrial oxidative stress in a STAT6–CREB–SOD2-dependent pathway in IgG4-RS.
文摘Pathological retinal neovascularization is the hallmark of primary blinding diseases across all age groups,yet surprisingly little is known about the causative factors.These diseases include diabetic retinopathy and retinopathy of prematurity where progressive decay of retinal vasculature yields zones of neural ischemia.These avascular zones and the hypoxic neurons and glia that reside in them are the source of pro-angiogenic factors that mediate destructive pre-retinal angiogenesis.Central neurons such as retinal ganglion cells(RGCs),which are directly apposed to degenerating vasculature in ischemic retinopathies,require stable metabolic supply for proper function.However,we unexpectedly found that RGCs are resilient to hypoxia/ischemia and a generally compromised metabolic supply and instead of degenerating,trigger protective mechanisms of cellular senescence.Paradoxically,while potentially favoring neuronal survival,the senescent state of RGCs is incompatible with vascular repair as they adopt a senescence-associated secretory phenotype(SASP)that provokes release of a secretome of inflammatory cytokines that drives paracrine senescence and further exacerbates pathological angiogenesis.The mechanisms that lead to retinal cellular senescence and dormancy as well as the therapeutic potential of targeting these pathways will be discussed.
基金supported by grants from the National Natural Science Foundation of China(No.82072979).
文摘Osteosarcoma is the most common primary malignancy of bones and primarily occurs in adolescents and young adults.However,a second smaller peak of osteosarcoma incidence was reported in the elderly aged more than 60.Elderly patients with osteosarcoma exhibit different characteristics compared to young patients,which usually results in a poor prognosis.The mechanism underlying osteosarcoma development in elderly patients is intriguing and of significant value in clinical applications.Senescent cells can accelerate tumor progression by metabolic reprogramming.Recent research has shown that methylmalonic acid(MMA)was significantly up-regulated in the serum of older individuals and played a central role in the development of aggressive characteristics.We found that the significant accumulation of MMA in elderly patients imparted proliferative potential to osteosarcoma cells.The expression of MAFB was excessively up-regulated in osteosarcoma specimens and was further enhanced in response to MMA accumulation as the patient aged.Specifically,we first confirmed a novel molecular mechanism between cellular senescence and cancer,in which the MMA-driven transcriptional reprogramming of the MAFB-NOTCH3 axis accelerated osteosarcoma progression via the activation of PI3K-AKT pathways.Moreover,the down-regulation of the MAFB-NOTCH3 axis increased the sensitivity and effect of AKT inhibitors in osteosarcoma through significant inhibition of AKT phosphorylation.In conclusion,we confirmed that MAFB is a novel age-dependent biomarker for osteosarcoma,and targeting the MAFB-NOTCH3 axis in combination with AKT inhibition can serve as a novel therapeutic strategy for elderly patients with osteosarcoma in experimental and clinical trials.
文摘Cellular senescence has emerged as an important contributor to aging and age-related diseases.Non-ionizing radiation(NIR),including ultraviolet radiation and electromagnetic fields,has been increasingly recognized as a key inducer of premature senescence.In this review,we discuss the molecular mechanisms of NIR-induced cellular senescence and its effects on aging and age-related diseases.We also summarize the modulation strategies for NIR-induced cellular senescence.A better understanding of the complex relationship between nonionizing radiation,cellular senescence and age-related pathology may lead to interventions to ameliorate radiation damage and delay aging.Further research is still needed to elucidate the precise mechanisms,dose-response effects,and to develop protective strategies against radiation-induced senescence.
基金supported by the grant awarded to R.G.from the Singapore Ministry of Education(partially supported by grants A-8001134-00-00 and MOE-T2EP30221-0011).
文摘Idiopathic pulmonary fibrosis(IPF)is a progressive fibrosing interstitial lung disease with high morbidity and mortality but unclear etiology and incomplete pathophysiological understandings,making the discovery of effective therapeutics arduous.Currently,two drugs,nintedanib and pirfenidone,are available for IPF treatment which can slow down the fibrotic scarring in the lung but are unable to provide disease resolution.Hence,further revelation of the molecular mechanisms of IPF is critical for the development of novel therapeutics.Isthmin-1(ISM1)is a secreted anti-inflammatory protein highly expressed in the mouse and human lung.Ism1^(-/-)mice presented spontaneous and progressive lung emphysema,as well as heightened acute lung injury(ALI)upon lipopolysaccharide(LPS)treatment with an accompanied increase of post-LPS-ALI pulmonary fibrosis.ISM1 is important for lung homeostasis with airway-delivered recombinant ISM1(rISM1)suppressing cigarette smoke-induced emphysema,LPS-ALI,and house-dust mites(HDM)-induced asthma-like symptoms in mice.However,the role of ISM1 in pulmonary fibrosis is yet to be clearly understood.In this work,we show that Ism1^(-/-)mice presented heightened bleomycin-induced pulmonary fibrosis(BIPF),with enhanced immune cell infiltration,myofibroblast accumulation,and collagen deposition.ISM1 deficiency also led to increased cellular senescence in mouse lungs,isolated primary alveolar type II epithelial cells,and primary lung fibroblasts upon bleomycin treatment.Ism1^(-/-)mice also showed delayed resolution of pulmonary fibrosis with reduced lipofibroblasts and downregulation of lipid synthesis-related genes.These results are in congruence with the RNA-seq data which demonstrated gene expression alterations in Ism1^(-/-)lung that are linked to predisposition to pulmonary fibrosis and dysregulation of lipid metabolism pathways.Gene expression analyses showed that Ism1 is similarly dysregulated in the lungs of BIPF and human IPF patients.These findings reveal an anti-fibrotic role of ISM1 in mouse lungs and provide the foundation to further investigate possible therapeutic applications of ISM1 for pulmonary fibrosis in the future.
基金supported by the Youth Thousand Talents Program of China,start-up grants from the Shanghai Jiao Tong University(No.WF220408211)supported by grants from the State Key Laboratory of Oncogenes and Related Genes(No.90-17-02)at Shanghai Jiao Tong Universityfrom the Interdisciplinary Program of Shanghai Jiao Tong University(China)(No.YG2017MS18).
文摘Hand-foot syndrome(HFS)is a widely recognized dose-limiting cutaneous toxicity effect of fluoropyrimidine chemotherapy agents that impairs clinical benefits and treatment outcomes.Even though the cause and pathophysiology of HFS are relatively widely reported,how the toxicity of fluoropyrimidine translates into persistent inflammation has not been studied.Additionally,prevention and treatment strategies for HFS based on its mechanistic occurrence and development are scarce.In our study,we demonstrated that cGAS-STING signaling pathway-mediated cellular senescence played a critical role in the inflammatory reaction and provided a therapeutic solution for HFS.Mechanistically,DNA damage,as the primary cytotoxic cause,in keratinocytes induces cell cycle arrest,activates the cGAS-STING signaling pathway,and subsequently mediates cellular senescence,ultimately fueling a robust secondary inflammatory response that results in HFS.More importantly,the thymidine prodrug thymidine diacetate was proven to be effective in preventing HFS by compensating for thymidylate deficiency to facilitate the replication and repair of DNA and thus causing the escape from cellular senescence.These data highlight the importance of DNA damage-mediated cellular senescence in the etiology of HFS and provide a potential therapeutic anchor point for fluoropyrimidine-induced HFS.
基金supported by the Key Program of the National Natural Science Foundation of China(82030056)the Intramural Research Project Grants(2021-JCJQ-ZD-077-11,AWS17J007 and 2018-JCJQ-ZQ-001)Postdoctoral Innovative Talent Support Program in Chongqing(CQBX2021010).
文摘Background:Radiation ulcers are a common and severe injury after uncontrolled exposure to ionizing radiation.The most important feature of radiation ulcers is progressive ulceration,which results in the expansion of radiation injury to the nonirradiated area and refractory wounds.Current theories cannot explain the progression of radiation ulcers.Cellular senescence refers to as irre-versible growth arrest that occurs after exposure to stress,which contributes to tissue dysfunction by inducing paracrine senescence,stem cell dysfunction and chronic inflammation.However,it is not yet clear how cellular senescence facilitates the continuous progression of radiation ulcers.Here,we aim to investigate the role of cellular senescence in promoting progressive radiation ulcers and indicate a potential therapeutic strategy for radiation ulcers.Methods:Radiation ulcer animal models were established by local exposure to 40 Gy X-ray radiation and continuously evaluated for>260 days.The roles of cellular senescence in the progression of radiation ulcers were assessed using pathological analysis,molecular detection and RNA sequencing.Then,the therapeutic effects of conditioned medium from human umbilical cord mesenchymal stem cells(uMSC-CM)were investigated in radiation ulcer models.Results:Radiation ulcer animal models with features of clinical patients were established to investigate the primary mechanisms responsible for the progression of radiation ulcers.We have characterized cellular senescence as being closely associated with the progression of radiation ulcers and found that exogenous transplantation of senescent cells significantly aggravated them.Mechanistic studies and RNA sequencing suggested that radiation-induced senescent cell secretions were responsible for facilitating paracrine senescence and promoting the progression of radiation ulcers.Finally,we found that uMSC-CM was effective in mitigating the progression of radiation ulcers by inhibiting cellular senescence.Conclusions:Our findings not only characterize the roles of cellular senescence in the progression of radiation ulcers but also indicate the therapeutic potential of senescent cells in their treatment.
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National Basic Research Program(973 Project) of China(Grant No.2007CB507406)the National Natural Science Foundation of China(Grant No.30572341)the Tsinghua-Yue-Yuen Medical Sciences Fund(THYY20070008)
文摘Echinacoside is one of the phenylethanoids isolated from the stems of Cistanches salsa. Our previous research showed that echinacoside has anti-senescence activity. To investigate the mechanism of echinacoside＇s anti-senescence activity, the expressions of p53, p21, p16 and Rb at the mRNA and protein levels were determined. Results showed that the expression of p53 was down-regulated significantly in a dose dependent manner after treatment with echinacoside. Further experiments suggested that the down-regulation of p53 may be correlated with the upregulation of SIRT1. In addition, echinacoside may exhibit considerable higher affinity towards SIRT1 than resveratrol, according to our molecular docking simulation. In conclusion, we expect that echinacoside might be a promising candidate for regulating cell senescence.
基金supported by the National Natural Science Foundation of China(No.31371341)Tsinghua University Initiative Scientific Research Program(No.20141081175)the Open Research Fund of State Key Laboratory of Bioelectronics,Southeast University
文摘Cellular senescence is an irreversible cell cycle arrest program in response to various exogenous and endogenous stimuli like telomere dysfunction and DNA damage.It has been widely accepted as an antitumor program and is also found closely related to embryo development,tissue repair,organismal aging and age-related degenerative diseases.In the past decades,numerous efforts have been made to uncover the gene regulatory mechanisms of cellular senescence.There is a strong demand to integrate these data from various resources into one open platform.To facilitate researchers on cellular senescence,we have developed Human Cellular Senescence Gene Database（HCSGD） by integrating multiple online published data sources into a comprehensive senescence gene annotation platform（http：//bioinfo.au.tsinghua.edu.cn/member/xwwang/HCSGD）.Potential Human Cellular Senescence Genes（HCSGS）were collected by combining information from published literatures,gene expression profiling data and Protein-Protein Interaction networks.Additionally,genes are annotated with gene ontology annotation and microRNA/drug/compound target information.HCSGD provides a valuable resource to visualize cellular senescence gene networks,browse annotated functional information,and retrieve senescenceassociated genes with a user-friendly web interface.
基金sponsored by grants from the National key R&D Program of China(No.2018YFA0108700,No.2017YFA0105602,No.2018YFA0108100)National Natural Science Foundation of China(No.81720108004,No.81974019,No.31871474)+4 种基金the Research Team Project of Natural Science Foundation of Guangdong Province of China(No.2017A030312007)Science and Technology Planning Project of Guangdong Province(No.2022B1212010010)the Key Program of Guangzhou Science Research Plan(No.201904020047)The Special Project of Dengfeng Program of Guangdong Provincial People’s Hospital(No.DFJH201812,No.KJ012019119,No.KJ012019423)the Shanghai Tech University start-up fund。
文摘Background Cellular senescence,an irreversible state of cell-cycle arrest triggered by multiple stress factors,plays a key role in organ development and wound healing.Accumulated senescent cells also promote tissue inflammation and involve in various diseases including myocardial infarction,atherosclerosis,diabetes and nonalcoholic steatohepatitis.Understanding the mechanism and consequences of cellular senescence is crucial to develop new therapies for diseases.Here,we describe the characteristics of senescent cells and involvement of senescent cardiac cells in heart development,regeneration and diseases.We summarize the work in this area and provide directions and clues for future studies.
基金supported by Dalian Youth Science and Technology Star Project(2020RQ121)the National Science Fund for Distinguished Young Scholars of China(31925031)+1 种基金Doctoral Scientific Research Foundation of Liaoning Province(2020-BS-211)Liaoning Province Education Administration(J2020101)。
文摘Cellular senescence is the results of aging and age-related diseases,and the development of anti-aging methods may improve health and extend longevity.The natural flavonol fisetin has been shown to antagonize senescence in vitro and increases longevity in vivo,but has poor water solubility and limited bioavailability.In this study,a food-grade and senescent cell-targeted delivery system for fisetin was developed based on whey protein isolate-galactooligosaccharides(WPI-GOS)Maillard conjugate,which could recognize senescence associatedβ-galactosidase in senescent cells.The fisetin nanoparticles possessed a high encapsulation efficiency,excellent dispersibility in water,good storage stability and well biocompatibility.Moreover,they could effectively accumulate and retain in senescent cells with excellent senescent cell-targeting efficacy,and inhibit the oxidative stress-induced cellular senescence in vitro.Thus,this novel nanoparticle system based on WPI-GOS Maillard conjugate showed promise to deliver hydrophobic bioactive ingredients like fisetin to senescent cells to improve their bioavailability and anti-senescence effect.
基金supported by grants from the National Natural Science Foundation of China(Nos.81370660,81170524)
文摘Summary： Senescence is an important obstacle to cancer development. Engaging a senescent response may be an effective way to cure acute myeloid leukemia （AML）. The aim of this study was to examine the effect of resveratrol-downregulated phosphorylated liver kinase B1 （pLKB1） on the senescence of acute myeloid leukemia （AML） stem cells. The protein expressions of pLKB 1 and Sirtuin 1 （SIRT1）, a regulator ofpLKB1, were measured in CD34＋CD38-KGla cells treated with resveratrol （40 μmol/L） or not by Western blotting. Senescence-related factors were examined, including p21 mRNA tested by real-time PCR, cell morphology by senescence-associated β-galactosidase （SA-β-gal） staining, cell pro- liferation by MTT assay and cell cycle by flow cytometry. Besides, apoptosis was flow cytometrically determined. The results showed that pLKB1 was highly expressed in CD34＋CD38- KGla cells, and resveratrol, which could downregulate pLKB1 through activation of SIRT1, induced senescence and apoptosis of CD34＋CD38- KGla cells. It was concluded that resveratrol-downregulated pLKB1 is in- volved in the senescence of AML stem cells.
基金Grants from the Liaoning Nature Science Foundation of China,Grant/Award Number:2022JH2/101300042National Natural Science Foundation of China,Grant/Award Numbers:81672877,82173194。
文摘The intrinsic oncogenic mechanisms and properties of the tumor microenvironment(TME)have been extensively investigated.Primary features of the TME include metabolic reprogramming,hypoxia,chronic inflammation,and tumor immunosuppression.Previous studies suggest that senescence-associated secretory phenotypes that mediate intercellular information exchange play a role in the dynamic evolution of the TME.Specifically,hypoxic adaptation,metabolic dysregulation,and phenotypic shifts in immune cells regulated by cellular senescence synergistically contribute to the development of an immunosuppressive microenvironment and chronic inflammation,thereby promoting the progression of tumor events.This review provides a comprehensive summary of the processes by which cellular senescence regulates the dynamic evolution of the tumor-adapted TME,with focus on the complex mechanisms underlying the relationship between senescence and changes in the biological functions of tumor cells.The available findings suggest that components of the TME collectively contribute to the progression of tumor events.The potential applications and challenges of targeted cellular senescence-based and combination therapies in clinical settings are further discussed within the context of advancing cellular senescence-related research.
基金supported by the Beijing Municipal Natural Science Foundation(7202139 and 7162137),China.
文摘Skin Exposure of skin to ionizing radiation can induce acute or chronic biological effects,resulting in radiation-induced skin injury(RSI).Premature cellular senescence,caused by oxidative stress and/or DNA damage from chemical or physical agents,leads to the decrease of cellular proliferation and physiological function.Persistent DNA damage and accumulation of senescent cells are associated with the progression of radiation-induced injury.Atopic dermatitis and RSI have similar inflammatory symptoms.The treatment of tacrolimus(TAC)in atopic dermatitis may be associated with premature cellular senescence.TAC can prevent the onset of cellular senes-cence by inactivating the p38 mitogen-activated protein kinase(p38 MAPK).The activation of p38 MAPK can induce the senescence-associated secretory phenotype(SASP)by enhancing the transcriptional activity of nuclear factor kappa-B(NF-κB),which ultimately leads to premature cellular senescence.FK506 binding protein 51(FKBP51)exhibits resistance to ionizing radiation,but the mechanism of TAC regulation of ionizing radiation-induced premature senescence still needs further study.This review discusses the mechanism of cellular senes-cence in RSI and the role of TAC in both dermatitis and RSI.
