BACKGROUND Cellular senescence is a recognized barrier for progression of chronic liver diseases to hepatocellular carcinoma(HCC). The expression of a cluster of genes is altered in response to environmental factors d...BACKGROUND Cellular senescence is a recognized barrier for progression of chronic liver diseases to hepatocellular carcinoma(HCC). The expression of a cluster of genes is altered in response to environmental factors during senescence. However, it is questionable whether these genes could serve as biomarkers for HCC patients.AIM To develop a signature of senescence-associated genes(SAGs) that predicts patients' overall survival(OS) to improve prognosis prediction of HCC.METHODS SAGs were identified using two senescent cell models. Univariate COX regression analysis was performed to screen the candidate genes significantly associated with OS of HCC in a discovery cohort(GSE14520) for the least absolute shrinkage and selection operator modelling. Prognostic value of this seven-gene signature was evaluated using two independent cohorts retrieved from the GEO(GSE14520) and the Cancer Genome Atlas datasets, respectively.Time-dependent receiver operating characteristic(ROC) curve analysis was conducted to compare the predictive accuracy of the seven-SAG signature and serum α-fetoprotein(AFP).RESULTS A total of 42 SAGs were screened and seven of them, including KIF18 B, CEP55,CIT, MCM7, CDC45, EZH2, and MCM5, were used to construct a prognostic formula. All seven genes were significantly downregulated in senescent cells andupregulated in HCC tissues. Survival analysis indicated that our seven-SAG signature was strongly associated with OS, especially in Asian populations, both in discovery and validation cohorts. Moreover, time-dependent ROC curve analysis suggested the seven-gene signature had a better predictive accuracy than serum AFP in predicting HCC patients' 1-, 3-, and 5-year OS.CONCLUSION We developed a seven-SAG signature, which could predict OS of Asian HCC patients. This risk model provides new clinical evidence for the accurate diagnosis and targeted treatment of HCC.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
Gradual alterations of cell’s physiology and functions due to age or exposure to various stresses lead to the conversion of normal cells to senescent cells.Once becoming senescent,the cell stops dividing permanently ...Gradual alterations of cell’s physiology and functions due to age or exposure to various stresses lead to the conversion of normal cells to senescent cells.Once becoming senescent,the cell stops dividing permanently but remains metabolically active.Cellular senescence does not have a single marker but is characterized mainly by a combination of multiple markers,such as,morphological changes,expression of cell cycle inhibitors,senescence associatedβ-galactosidase activity,and changes in nuclear membrane.When cells in an organ become senescent,the entire organism can be affected.This may occur through the senescence-associated secretory phenotype(SASP).SASP may exert beneficial or harmful effects on the microenvironment of tissues.Research on senescence has become a very exciting field in cell biology since the link between age-related diseases,including cancer,and senescence has been established.The loss of regenerative and homeostatic capacity of the liver over the age is somehow connected to cellular senescence.The major contributors of senescence properties in the liver are hepatocytes and cholangiocytes.Senescent cells in the liver have been implicated in the etiology of chronic liver diseases including cirrhosis and hepatocellular carcinoma and in the interference of liver regeneration.This review summarizes recently reported findings in the understanding of the molecular mechanisms of senescence and its relationship with liver diseases.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
An enriched environment protects dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP）-induced neuronal injury, but the underlying mechanism for this is not clear. Growth associated protein-43...An enriched environment protects dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP）-induced neuronal injury, but the underlying mechanism for this is not clear. Growth associated protein-43（GAP-43） is closely associated with neurite outgrowth and axon regeneration during neural development. We speculate that an enriched environment can reduce damage to dopaminergic neurons by affecting the expression of GAP-43. This study is designed to test this hypothesis. Three-month-old female senescence-accelerated mouse prone 8（SAMP8） mice were housed for 3 months in an enriched environment or a standard environment. These mice were then subcutaneously injected in the abdomen with 14 mg/kg MPTP four times at 2-hour intervals. Morris water maze testing demonstrated that learning and memory abilities were better in the enriched environment group than in the standard environment group. Reverse-transcription polymerase chain reaction, immunohistochemistry and western blot assays showed that m RNA and protein levels of GAP-43 in the substantia nigra were higher after MPTP application in the enriched environment group compared with the standard environment group. These findings indicate that an enriched environment can increase GAP-43 expression in SAMP8 mice. The upregulation of GAP-43 may be a mechanism by which an enriched environment protects against MPTP-induced neuronal damage.展开更多
Aging-related diseases are gradually becoming a major problem with the rapid development of aged population in human society.Although many fluorescent probes have been employed to diagnosis senescence via imaging sene...Aging-related diseases are gradually becoming a major problem with the rapid development of aged population in human society.Although many fluorescent probes have been employed to diagnosis senescence via imaging senescence-associatedβ-galactosidase(SA-β-Gal),which is proved to be closely associated with senescent cells,the similar catalytic effectiveness of enzymatic reaction of ovarian cancer-associatedβ-Gal(OA-β-Gal)will interfere with imaging accuracy.Herein,a near-infrared(NIR)hemicyanine based fluorescent probe HCyXA-βGal was designed for light-up imaging of live cells containingβ-Gal.With the organelle-targeting morpholinyl and positive charge moieties,HCyxA-βGal was successfully applicated to image the difference of enzymatic location in senescent cells and ovarian cancer cells.Furthermore,inspired by the fast response performance,fast and precise imaging of the two cell lines was realized via covering another dimension of fluorescence signal:time-dependent intensity.展开更多
基金Supported by the National Natural Science Foundation of China,No.81773128 and No.81871998the Natural Science Basic Research Plan in Shaanxi Province of China,No.2018JM7013 and No.2017JM8039+1 种基金the Research Fund for Young Star of Science and Technology in Shaanxi Province,No.2018KJXX-022China Postdoctoral Science Foundation,No.2018M641000
文摘BACKGROUND Cellular senescence is a recognized barrier for progression of chronic liver diseases to hepatocellular carcinoma(HCC). The expression of a cluster of genes is altered in response to environmental factors during senescence. However, it is questionable whether these genes could serve as biomarkers for HCC patients.AIM To develop a signature of senescence-associated genes(SAGs) that predicts patients' overall survival(OS) to improve prognosis prediction of HCC.METHODS SAGs were identified using two senescent cell models. Univariate COX regression analysis was performed to screen the candidate genes significantly associated with OS of HCC in a discovery cohort(GSE14520) for the least absolute shrinkage and selection operator modelling. Prognostic value of this seven-gene signature was evaluated using two independent cohorts retrieved from the GEO(GSE14520) and the Cancer Genome Atlas datasets, respectively.Time-dependent receiver operating characteristic(ROC) curve analysis was conducted to compare the predictive accuracy of the seven-SAG signature and serum α-fetoprotein(AFP).RESULTS A total of 42 SAGs were screened and seven of them, including KIF18 B, CEP55,CIT, MCM7, CDC45, EZH2, and MCM5, were used to construct a prognostic formula. All seven genes were significantly downregulated in senescent cells andupregulated in HCC tissues. Survival analysis indicated that our seven-SAG signature was strongly associated with OS, especially in Asian populations, both in discovery and validation cohorts. Moreover, time-dependent ROC curve analysis suggested the seven-gene signature had a better predictive accuracy than serum AFP in predicting HCC patients' 1-, 3-, and 5-year OS.CONCLUSION We developed a seven-SAG signature, which could predict OS of Asian HCC patients. This risk model provides new clinical evidence for the accurate diagnosis and targeted treatment of HCC.
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Gradual alterations of cell’s physiology and functions due to age or exposure to various stresses lead to the conversion of normal cells to senescent cells.Once becoming senescent,the cell stops dividing permanently but remains metabolically active.Cellular senescence does not have a single marker but is characterized mainly by a combination of multiple markers,such as,morphological changes,expression of cell cycle inhibitors,senescence associatedβ-galactosidase activity,and changes in nuclear membrane.When cells in an organ become senescent,the entire organism can be affected.This may occur through the senescence-associated secretory phenotype(SASP).SASP may exert beneficial or harmful effects on the microenvironment of tissues.Research on senescence has become a very exciting field in cell biology since the link between age-related diseases,including cancer,and senescence has been established.The loss of regenerative and homeostatic capacity of the liver over the age is somehow connected to cellular senescence.The major contributors of senescence properties in the liver are hepatocytes and cholangiocytes.Senescent cells in the liver have been implicated in the etiology of chronic liver diseases including cirrhosis and hepatocellular carcinoma and in the interference of liver regeneration.This review summarizes recently reported findings in the understanding of the molecular mechanisms of senescence and its relationship with liver diseases.
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 a grant from the Health Department of Hebei Province of China,No.20120056,20140314the Funding Project for Introduced Abroad Study Personnel of Hebei Province of China,No.C2011003039
文摘An enriched environment protects dopaminergic neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine（MPTP）-induced neuronal injury, but the underlying mechanism for this is not clear. Growth associated protein-43（GAP-43） is closely associated with neurite outgrowth and axon regeneration during neural development. We speculate that an enriched environment can reduce damage to dopaminergic neurons by affecting the expression of GAP-43. This study is designed to test this hypothesis. Three-month-old female senescence-accelerated mouse prone 8（SAMP8） mice were housed for 3 months in an enriched environment or a standard environment. These mice were then subcutaneously injected in the abdomen with 14 mg/kg MPTP four times at 2-hour intervals. Morris water maze testing demonstrated that learning and memory abilities were better in the enriched environment group than in the standard environment group. Reverse-transcription polymerase chain reaction, immunohistochemistry and western blot assays showed that m RNA and protein levels of GAP-43 in the substantia nigra were higher after MPTP application in the enriched environment group compared with the standard environment group. These findings indicate that an enriched environment can increase GAP-43 expression in SAMP8 mice. The upregulation of GAP-43 may be a mechanism by which an enriched environment protects against MPTP-induced neuronal damage.
基金supported by National Natural Science Foundation of China(Nos.22122803 and 21788102)the National Natural Science Foundation of Jiangsu Province(No.BK20220644).
文摘Aging-related diseases are gradually becoming a major problem with the rapid development of aged population in human society.Although many fluorescent probes have been employed to diagnosis senescence via imaging senescence-associatedβ-galactosidase(SA-β-Gal),which is proved to be closely associated with senescent cells,the similar catalytic effectiveness of enzymatic reaction of ovarian cancer-associatedβ-Gal(OA-β-Gal)will interfere with imaging accuracy.Herein,a near-infrared(NIR)hemicyanine based fluorescent probe HCyXA-βGal was designed for light-up imaging of live cells containingβ-Gal.With the organelle-targeting morpholinyl and positive charge moieties,HCyxA-βGal was successfully applicated to image the difference of enzymatic location in senescent cells and ovarian cancer cells.Furthermore,inspired by the fast response performance,fast and precise imaging of the two cell lines was realized via covering another dimension of fluorescence signal:time-dependent intensity.
