Aging increases the risks of various diseases and the vulnerability to death.Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases.This study demonstrates that extrace...Aging increases the risks of various diseases and the vulnerability to death.Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases.This study demonstrates that extracellular vesicles from human urine-derived stem cells(USC-EVs)efficiently inhibit cellular senescence in vitro and in vivo.The intravenous injection of USC-EVs improves cognitive function,increases physical fitness and bone quality,and alleviates aging-related structural changes in different organs of senescence-accelerated mice and natural aging mice.The anti-aging effects of USC-EVs are not obviously affected by the USC donors’ages,genders,or health status.Proteomic analysis reveals that USC-EVs are enriched with plasminogen activator urokinase(PLAU)and tissue inhibitor of metalloproteinases 1(TIMP1).These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases,cyclin-dependent kinase inhibitor 2A(P16INK4a),and cyclin-dependent kinase inhibitor 1A(P21cip1).These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.展开更多
BACKGROUND; Polymorphisms of urokinase-type plasminogen activator gene （PLAU） have recently been reported to be associated with sporadic Alzheimer＇ disease （SAD）. However, most studies have focused on the exon re...BACKGROUND; Polymorphisms of urokinase-type plasminogen activator gene （PLAU） have recently been reported to be associated with sporadic Alzheimer＇ disease （SAD）. However, most studies have focused on the exon region of this gene, and there is no report on the association between promoter polymorphisms of the PLAU and SAD. OBJECTIVE： To determine whether SAD is associated with promoter polymorphisms of PLAU in Northem Han Chinese. DESIGN, TIME AND SETTING： A case-control study was performed at Neurology Laboratory of Xuanwu Hospital of the Capital Medical University from September 2006 to July 2008. PARTICIPANTS： A total of 397 participants living in Beijing were assigned to SAD [n = 196, including 103 males and 93 females, mean age of （64 ± 7） years] and control [n = 201, including 108 males and 93 females, mean age of （68 ± 6） years] groups. The patients were diagnosed and met the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer＇s Disease and Related Disorder Association criteria for possible Alzheimer＇s disease. Controls received clinical, mental, and neurological examinations to rule out cognitive deficiencies. All controls had Mini-Mental Status Examination scores 〉 27. METHODS： Genotypes of PLAU and apolipoprotein-E were examined in 196 patients with SAD and 201 age- and sex-matched controls from the same community using polymerase chain reaction-restriction fragment length polymorphism method. SPSS 11.5 software was used for data analysis, distribution of allele and genotypic frequency were calculated, and Hardy-Weinberg was also performed in this study. MAIN OUTCOME MEASURES： The main outcome measures were allele and genotype frequency differences in the promoter region of the PLAU gene between SAD and control subjects. RESULTS： In Chinese Han populations, the two polymorphisms in PLAU promoter were -25 C/T （rs2227579） and 43 G/T （rs2227580）. Detection of these promoter polymorphisms revealed significant differences in allele and genotype frequency for -25 CfT and 43 G/T when 196 SAD patients were compared with 201 controls （P〈 0.05）. Logistic analyses indicated that, compared with C/T and T/T genotypes, the -25 C/C genotype resulted in a 1.5-fold risk for developing SAD （adjusted odds ratio = 1.510, 95% confidence interval： 0.198 2.281, P= 0.010）, while the 43G/G genotype resulted in a 1.3-fold risk for SAD （adjusted odds ratio = 1.300, 95% confidence interval： 0.178 2.051, P= 0.030）. CONCLUSION： The present study provided evidence that promoter polymorphisms of PLAU are associated with development of SAD in Northern Han Chinese.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.82125023,82072504,81871822,82172501,81801395,and 82200039)the Science and Technology Innovation Program of Hunan Province(Grant Nos.2020RC4008 and 2022RC1211,China)+4 种基金the China National Postdoctoral Program for Innovative Talents(Grant No.BX2021383,China)the Central South University InnovationDriven Research Programme(Grant Nos.2023CXQD001 and 2019CX014,China)the Hunan Province Natural Science Foundation of China(Grant Nos.2023JJ10094 and 2020JJ5883)the Youth Science Foundation of Xiangya Hospital(Grant No.2022Q07,China)the Hunan Provincial Innovation Foundation for Postgraduate(Grant Nos.2021ZZTS0342 and 2022ZZTS0239,China)。
文摘Aging increases the risks of various diseases and the vulnerability to death.Cellular senescence is a hallmark of aging that contributes greatly to aging and aging-related diseases.This study demonstrates that extracellular vesicles from human urine-derived stem cells(USC-EVs)efficiently inhibit cellular senescence in vitro and in vivo.The intravenous injection of USC-EVs improves cognitive function,increases physical fitness and bone quality,and alleviates aging-related structural changes in different organs of senescence-accelerated mice and natural aging mice.The anti-aging effects of USC-EVs are not obviously affected by the USC donors’ages,genders,or health status.Proteomic analysis reveals that USC-EVs are enriched with plasminogen activator urokinase(PLAU)and tissue inhibitor of metalloproteinases 1(TIMP1).These two proteins contribute importantly to the anti-senescent effects of USC-EVs associated with the inhibition of matrix metalloproteinases,cyclin-dependent kinase inhibitor 2A(P16INK4a),and cyclin-dependent kinase inhibitor 1A(P21cip1).These findings suggest a great potential of autologous USC-EVs as a promising anti-aging agent by transferring PLAU and TIMP1 proteins.
基金the National Key Technology R&D Program in the Eleventh Five-year Plan Period,No.2006BAI02B01the National Basic Research 973 Program,No.2006CB500700+1 种基金the Beijing Natural Science Foundation,No.7071004Funding Project for Academic Human Resources Development in Institutions of Higher Learning Under the Jurisdiction of Beijing Municipality
文摘BACKGROUND; Polymorphisms of urokinase-type plasminogen activator gene （PLAU） have recently been reported to be associated with sporadic Alzheimer＇ disease （SAD）. However, most studies have focused on the exon region of this gene, and there is no report on the association between promoter polymorphisms of the PLAU and SAD. OBJECTIVE： To determine whether SAD is associated with promoter polymorphisms of PLAU in Northem Han Chinese. DESIGN, TIME AND SETTING： A case-control study was performed at Neurology Laboratory of Xuanwu Hospital of the Capital Medical University from September 2006 to July 2008. PARTICIPANTS： A total of 397 participants living in Beijing were assigned to SAD [n = 196, including 103 males and 93 females, mean age of （64 ± 7） years] and control [n = 201, including 108 males and 93 females, mean age of （68 ± 6） years] groups. The patients were diagnosed and met the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer＇s Disease and Related Disorder Association criteria for possible Alzheimer＇s disease. Controls received clinical, mental, and neurological examinations to rule out cognitive deficiencies. All controls had Mini-Mental Status Examination scores 〉 27. METHODS： Genotypes of PLAU and apolipoprotein-E were examined in 196 patients with SAD and 201 age- and sex-matched controls from the same community using polymerase chain reaction-restriction fragment length polymorphism method. SPSS 11.5 software was used for data analysis, distribution of allele and genotypic frequency were calculated, and Hardy-Weinberg was also performed in this study. MAIN OUTCOME MEASURES： The main outcome measures were allele and genotype frequency differences in the promoter region of the PLAU gene between SAD and control subjects. RESULTS： In Chinese Han populations, the two polymorphisms in PLAU promoter were -25 C/T （rs2227579） and 43 G/T （rs2227580）. Detection of these promoter polymorphisms revealed significant differences in allele and genotype frequency for -25 CfT and 43 G/T when 196 SAD patients were compared with 201 controls （P〈 0.05）. Logistic analyses indicated that, compared with C/T and T/T genotypes, the -25 C/C genotype resulted in a 1.5-fold risk for developing SAD （adjusted odds ratio = 1.510, 95% confidence interval： 0.198 2.281, P= 0.010）, while the 43G/G genotype resulted in a 1.3-fold risk for SAD （adjusted odds ratio = 1.300, 95% confidence interval： 0.178 2.051, P= 0.030）. CONCLUSION： The present study provided evidence that promoter polymorphisms of PLAU are associated with development of SAD in Northern Han Chinese.
