目的从细胞衰老研究中最常用的p16和p21两种不同表达特征出发,探讨2型糖尿病小鼠体内骨皮质与骨髓的衰老异质性及异步性,并研究不同抗衰老治疗方法的疗效差异。方法利用p21-3MR小鼠模型建立2型糖尿病模型,以股骨为例分析了2型糖尿病骨...目的从细胞衰老研究中最常用的p16和p21两种不同表达特征出发,探讨2型糖尿病小鼠体内骨皮质与骨髓的衰老异质性及异步性,并研究不同抗衰老治疗方法的疗效差异。方法利用p21-3MR小鼠模型建立2型糖尿病模型,以股骨为例分析了2型糖尿病骨组织的衰老模式,重点研究p16和p21在糖尿病病程中的异质性及异步性。通过槲皮素结合达沙替尼(dasatinib and quercetin,D+Q)和单纯干预p21两种方法评估抗衰老疗效。结果糖尿病病程中骨皮质与骨髓衰老呈现显著异质性与异步性,骨髓衰老以p21相关性为主且出现较早,而骨皮质衰老则与p16表达密切相关。不同治疗方法在骨皮质和骨髓中表现出显著差异,D+Q治疗在骨皮质中效果更优,而单纯干预p21在骨髓中效果显著。结论骨皮质与骨髓组织衰老异质性显著,且不同治疗方法各具特点,为糖尿病骨衰老干预提供新视角。展开更多
Background Abdominal aortic aneurysm(AAA)is a life-threatening vascular disease associated with endothelial cell senescence.Resveratrol(RSV),a natural polyphenol,exerts potent anti-senescent and anti-inflammatory effe...Background Abdominal aortic aneurysm(AAA)is a life-threatening vascular disease associated with endothelial cell senescence.Resveratrol(RSV),a natural polyphenol,exerts potent anti-senescent and anti-inflammatory effects.However,its molecular mechanism in treating AAA remains unclear.Methods An AAA model was established in mice via angiotensin Ⅱ(AngⅡ)infusion[1000 ng/(kg·min)],with a subset receiving RSV treatment[100 mg/(kg·day)by gavage].Aortic diameter was measured,and histopathological changes were assessed by Hematoxylin-Eosin(HE)and Elastica Van Gieson(EVG)staining.Vascular aging was evaluated by senescence-associatedβ-galactosidase(SA-β-gal)activity and pulse wave velocity(PWV).In vitro,human umbilical vein endothelial cells(HUVECs)were treated with AngⅡ(10-6 M)with or without RSV(40μM)and/or the sirtuin 1(SIRT1)inhibitor EX527(10μM).Senescence markers,senescence-associated secretory phenotype(SASP)factor expression[interleukin-1 beta(IL-1β),interleukin-6(IL-6),tumor necrosis factor-alpha(TNF-α)],and SIRT1/p21 pathway proteins were analyzed.Results In vivo,RSV significantly attenuated Ang Ⅱ-induced AAA formation,reducing aortic diameter,preserving elastic fiber integrity,and suppressing vascular senescence and stiffness.In HUVECs,Ang Ⅱ-induced senescence and SASP expression were markedly inhibited by RSV.However,these protective effects were abolished by EX527.Mechanistically,RSV reversed the Ang Ⅱ-induced downregulation of SIRT1 and upregulation of p21,which was also blocked by SIRT1 inhibition.Conclusions RSV effectively prevented experimental AAA formation by alleviating vascular aging and endothelial cell senescence.This protective effect was abrogated by the SIRT1 inhibitor EX527,confirming that RSV mitigated AAA development and vascular senescence through the SIRT1/p21 signaling pathway.These findings highlighted RSV as a promising therapeutic candidate for AAA treatment.展开更多
文摘目的从细胞衰老研究中最常用的p16和p21两种不同表达特征出发,探讨2型糖尿病小鼠体内骨皮质与骨髓的衰老异质性及异步性,并研究不同抗衰老治疗方法的疗效差异。方法利用p21-3MR小鼠模型建立2型糖尿病模型,以股骨为例分析了2型糖尿病骨组织的衰老模式,重点研究p16和p21在糖尿病病程中的异质性及异步性。通过槲皮素结合达沙替尼(dasatinib and quercetin,D+Q)和单纯干预p21两种方法评估抗衰老疗效。结果糖尿病病程中骨皮质与骨髓衰老呈现显著异质性与异步性,骨髓衰老以p21相关性为主且出现较早,而骨皮质衰老则与p16表达密切相关。不同治疗方法在骨皮质和骨髓中表现出显著差异,D+Q治疗在骨皮质中效果更优,而单纯干预p21在骨髓中效果显著。结论骨皮质与骨髓组织衰老异质性显著,且不同治疗方法各具特点,为糖尿病骨衰老干预提供新视角。
基金This work was supported by the National Natural Science Foundation of China (No. 30371753)the Research Project of Hebei Education Department (No. 2004110)the Doctor Foundation of Hebei Normal University (No. L2005B25)
基金supported by the grant from the Fujian Province Natural Science Foundation(No.2024J01608)。
文摘Background Abdominal aortic aneurysm(AAA)is a life-threatening vascular disease associated with endothelial cell senescence.Resveratrol(RSV),a natural polyphenol,exerts potent anti-senescent and anti-inflammatory effects.However,its molecular mechanism in treating AAA remains unclear.Methods An AAA model was established in mice via angiotensin Ⅱ(AngⅡ)infusion[1000 ng/(kg·min)],with a subset receiving RSV treatment[100 mg/(kg·day)by gavage].Aortic diameter was measured,and histopathological changes were assessed by Hematoxylin-Eosin(HE)and Elastica Van Gieson(EVG)staining.Vascular aging was evaluated by senescence-associatedβ-galactosidase(SA-β-gal)activity and pulse wave velocity(PWV).In vitro,human umbilical vein endothelial cells(HUVECs)were treated with AngⅡ(10-6 M)with or without RSV(40μM)and/or the sirtuin 1(SIRT1)inhibitor EX527(10μM).Senescence markers,senescence-associated secretory phenotype(SASP)factor expression[interleukin-1 beta(IL-1β),interleukin-6(IL-6),tumor necrosis factor-alpha(TNF-α)],and SIRT1/p21 pathway proteins were analyzed.Results In vivo,RSV significantly attenuated Ang Ⅱ-induced AAA formation,reducing aortic diameter,preserving elastic fiber integrity,and suppressing vascular senescence and stiffness.In HUVECs,Ang Ⅱ-induced senescence and SASP expression were markedly inhibited by RSV.However,these protective effects were abolished by EX527.Mechanistically,RSV reversed the Ang Ⅱ-induced downregulation of SIRT1 and upregulation of p21,which was also blocked by SIRT1 inhibition.Conclusions RSV effectively prevented experimental AAA formation by alleviating vascular aging and endothelial cell senescence.This protective effect was abrogated by the SIRT1 inhibitor EX527,confirming that RSV mitigated AAA development and vascular senescence through the SIRT1/p21 signaling pathway.These findings highlighted RSV as a promising therapeutic candidate for AAA treatment.
