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71.
Brittain NJ Erexson C Faucette L Ward J Fujioka H Wellems TE Fairhurst RM 《British journal of haematology》2007,136(3):491-500
Haemoglobin C (HbC) differs from normal HbA by a lysine for glutamate substitution at position 6 of beta-globin. Heterozygous AC and homozygous CC phenotypes are associated with shortened erythrocyte life spans and mild anaemia. AC and CC erythrocytes contain elevated amounts of membrane-associated haemichromes, band 3 clusters, and immunoglobulin G (IgG) in vivo. These findings led us to investigate whether AC and CC erythrocytes might expose elevated levels of IgG and complement, two opsonins that have been implicated in the phagocytic clearance of senescent and sickle erythrocytes. Surprisingly, we found IgG, complement, and other plasma proteins co-localised in aggregates beneath the membrane of circulating AC and CC erythrocytes. These observations, and our finding of similar aggregates in erythrocytes heterozygous or homozygous for haemoglobin S (sickle-cell haemoglobin), suggest that the vast majority of membrane-associated IgG and complement detected in these abnormal erythrocytes is intracellular and does not contribute to the eventual opsonic clearance of these cells. Phagocytosis studies with macrophages provide evidence in support of this suggestion. Studies of erythrocyte clearance that involve the detection of membrane-associated IgG and complement as putative opsonins should investigate the possibility that these plasma proteins reside in the erythrocyte interior, and not on the cell surface. 相似文献
72.
Jansen-Dürr P 《Experimental gerontology》2000,35(9-10):1151-1155
Human aging is correlated with reduced proliferation of various cell types, a phenomenon that can be reproduced in in vitro models of replicative senescence. We study senescence of several human primary cell types by analysis of age-related changes in gene expression and gene function. In a second approach, my group uses immortalizing oncogenes derived from DNA tumor viruses as genetic tools to study genetic and biochemical mechanisms underlying the progression of cells into senescence. Specifically, our work is guided by the hypothesis that cellular proteins binding to the E7 gene product of human papillomavirus are good candidates for senescence-inducing cellular factors. For several of these cellular factors, e.g. the inhibitor of cyclin-dependent kinases p21(WAF-1), a functional role in senescence has already been demonstrated. 相似文献
73.
目的:探讨十两茶提取物对氧化型低密度脂蛋白(ox-LDL)诱导衰老细胞模型的影响及其可能的机制。方法将人脐静脉内皮细胞(HUVECs)株于含有10%牛血清的DMEM培养液中培养,使用ox-LDL孵育建立衰老细胞模型,用β?半乳糖苷酶染色法评价内皮细胞的衰老状态,分别予以不同剂量十两茶提取物及辛伐他汀预处理,检测培养液中活性氧(ROS)、非对称二甲基精氨酸(ADMA)、二甲基精氨酸二甲胺水解酶(DDAH)以及端粒酶活性水平。结果 ox-LDL诱导的内皮细胞衰老模型中β?半乳糖苷酶染色阳性的细胞数量显著增加,细胞内ROS水平、ADMA水平增强,DDAH和端粒酶活性降低,而十两茶提取物预处理可明显抑制这一过程(P<0.05)。结论十两茶提取物在ox-LDL诱导的内皮细胞衰老进程中起抑制作用,其机制可能与降低细胞内ROS、ADMA水平以及提高DDAH水平和端粒酶活性有关。 相似文献
74.
75.
Ziying Yang Xuan Liu Longgang Wang Tao Wang Yueqiu Chen Xiaomei Teng Jingjing Li Lianbo Shao Jie Hui Wenxue Ye Zhenya Shen 《Journal of tissue engineering and regenerative medicine》2020,14(4):588-599
Bone marrow‐derived mesenchymal stromal cells (MSCs) have been wildly applied to cell‐based strategies for tissue engineering and regenerative medicine; however, they have to undergo the senescence process and thus appeared to be less therapeutic effective. HMGA2, a protein belonged to high mobility group A (HMGA) family, exhibits an inverse expression level related to embryonic development and acts as a developmental regulator in stem cell self‐renewal progression. Therefore, we performed senescence‐associated β‐galactosidase (SA‐β‐gal) staining, transwell assay, to examine the changes of MSCs in different stages and then over‐expressed HMGA2 in MSCs by lentivirus transfection. We found the percentage of SA‐β‐gal staining positive cells in MSCs from 24‐month‐old Sprague–Dawley (SD) rats (O‐MSCs) was significantly higher compared with MSCs from 2‐week‐old SD rats (Y‐MSCs), and the expression levels of P21 and P53, two senescence‐related molecules, were also significantly up‐regulated in O‐MSCs than in Y‐MSCs. In contrast, the HMGA2 expression level in O‐MSCs was dramatically down‐regulated in contrast to Y‐MSCs. In additional, the migration ability in O‐MSCs was significantly attenuated than in Y‐MSCs. After successfully over‐expressed HMGA2 in O‐MSCs, the percentage of SA‐β‐gal staining positive cells and the expression levels of P21 and P53 were reduced, and the migration ability was improved compared with O‐MSCs without treatment. Further, mRNA sequencing analysis revealed that overexpression of HMGA2 changed the expression of genes related to cell proliferation and senescence, such as Lyz2, Pf4, Rgs2, and Mstn. Knockdown of Rgs2 in HMGA2 overexpression O‐MSCs could antagonize the protective effect of HMGA2 in the senescence process of O‐MSCs. 相似文献
76.
Brandon P. Verdoorn MD Tamara K. Evans BS Gregory J. Hanson MD Yi Zhu PhD Larissa G. P. Langhi Prata PhD Robert J. Pignolo MD PhD Elizabeth J. Atkinson MS Erin O. Wissler-Gerdes MA George A. Kuchel MD Joan B. Mannick MD Stephen B. Kritchevsky PhD Sundeep Khosla MD Stacey A. Rizza MD Jeremy D. Walston MD Nicolas Musi MD Lewis A. Lipsitz MD Douglas P. Kiel MD Raymond Yung MB ChB Nathan K. LeBrasseur PhD Ravinder J. Singh PhD Teresa McCarthy MD MS Michael A. Puskarich MD Laura J. Niedernhofer MD PhD Paul D. Robbins PhD Matthew Sorenson JD MA Tamara Tchkonia PhD James L. Kirkland MD PhD 《Journal of the American Geriatrics Society》2021,69(11):3023-3033
The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS-CoV-2 infection. SARS-CoV-2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence-associated secretory phenotype (SASP). The SASP can be amplified by infection-related pathogen-associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS-CoV-2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS-CoV-2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health-funded, multicenter, placebo-controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS-CoV-2 rtPCR-positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long-term care settings in the SARS-CoV-2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials. 相似文献
77.
78.
Kaitlyn C. Leonard Marissa L. Boettcher Edwin Dickinson Neha Malhotra Fabienne Aujard Anthony Herrel Adam Hartstone-Rose 《Anatomical record (Hoboken, N.J. : 2007)》2020,303(5):1364-1373
The masticatory apparatus has been the focus of many studies in comparative anatomy—especially analyses of skulls and teeth, but also of the mandibular adductor muscles which are responsible for the production of bite force and the movements of the mandible during food processing and transport. The fiber architecture of these muscles has been correlated to specific diets (e.g., prey size in felids) and modes of foraging (e.g., tree gouging in marmosets). Despite the well-elucidated functional implications of this architecture, little is known about its ontogeny. To characterize age-related myological changes, we studied the masticatory muscles in a large (n = 33) intraspecific sample of a small, Malagasy primate, Microcebus murinus including neonatal through geriatric individuals. We removed each of the mandibular adductors and recorded its mass as well as other linear measurements. We then chemically dissected each muscle to study its architecture—fascicle length and physiological cross-sectional area (PCSA) which relate to stretch (gape) and force capabilities, respectively. We observed PCSA and muscle mass to increase rapidly and plateau in adulthood through senescence. Fascicle lengths remained relatively constant once maximal length was reached, which occurred early in life, suggesting that subsequent changes in PCSA are driven by changes in muscle mass. Quadratic curvilinear models of each of the architectural variables of all adductors combined as well as individual muscles regressed against age were all significant. Anat Rec, 303:1364–1373, 2020. © 2019 American Association for Anatomy 相似文献
79.
Human diploid fibroblasts (HDFs) exposed to subcytotoxic concentrations of oxidative or stressful agents, such as hydrogen peroxide, tert-butylhydroperoxide, or ethanol, undergo stress-induced premature senescence (SIPS). This condition is characterized by the appearance of replicative senescence biomarkers such as irreversible growth arrest, increase in senescence-associated β-galactosidase (SA β-gal) activity, altered cell morphology, and overexpression of several senescence-associated genes. Copper is an essential trace element known to accumulate with ageing and to be involved in the pathogenesis of some age-related disorders. Past studies using either yeast or human cellular models of ageing provided evidence in favor of the role of intracellular copper as a longevity modulator. In the present study, copper ability to cause the appearance of senescent features in HDFs was assessed. WI-38 fibroblasts exposed to a subcytotoxic concentration of copper sulfate presented inhibition of cell proliferation, cell enlargement, increased SA β-gal activity, and mRNA overexpression of several senescence-associated genes such as p21, apolipoprotein J (ApoJ), fibronectin, transforming growth factor β-1 (TGF β1), insulin growth factor binding protein 3, and heme oxygenase 1. Western blotting results confirmed enhanced intracellular p21, ApoJ, and TGF β1 in copper-treated cells. Thus, similar to other SIPS-inducing agents, HDF exposure to subcytotoxic concentration of copper results in premature senescence. Further studies will unravel molecular mechanisms and the biological meaning of copper-associated senescence and lead to a better understanding of copper-related disorder establishment and progression.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9276-7) contains supplementary material, which is available to authorized users. 相似文献80.
目的:血管内皮细胞衰老是动脉粥样硬化发生的病理生理机制之一。本研究旨在探讨人参皂苷Rb1延缓人脐静脉内皮细胞(HUVECs)早熟性衰老与窖蛋白1(caveolin-1)表达的关系,为延缓HUVECs衰老提供新的靶点。方法:建立60μmol/L过氧化氢(H_2O_2)诱导的HUVECs早熟性衰老模型,根据细胞形态学的变化、衰老相关β-半乳糖苷酶(SA-β-Gal)染色阳性率和细胞周期评估内皮细胞衰老,采用Western blot和激光共聚焦显微成像的方法检测caveolin-1的变化,观察人参皂苷Rb1对HUVECs衰老的作用及其相关的分子机制。结果:60μmol/L H_2O_2可成功地诱导内皮细胞衰老,早熟性衰老的HUVECs体积变大,SA-β-Gal活性明显增加,细胞发生G_1期阻滞,细胞增殖受抑制,caveolin-1表达增多。与H_2O_2处理组相比,人参皂苷Rb1预处理延缓HUVECs早熟性衰老,SA-β-Gal染色阳性细胞百分比降低,G_0/G_1期细胞比例下降,caveolin-1表达减少。结论:人参皂苷Rb1可通过抑制caveolin-1的表达延缓H_2O_2诱导的HUVECs早熟性衰老。 相似文献