Elevated p53 expression in benign meningiomas protects against recurrence and may be indicative of senescence

Prediction of recurrence after resection of benign meningiomas represents a significant clinical problem. A prospective study commenced in 1984 aimed to elucidate the molecular mechanisms involved in the development of abnormal karyotype and tumour recurrence in meningiomas. Expression of key cell cycle regulators p53, p21, mdm2 and proliferating cell nuclear antigen (PCNA) were studied by immunohistochemistry in 85 tumours for which follow-up data was available. It was found that most tumours expressed p53, p21 and PCNA, with significant correlations between expression of p53 and both p21 and PCNA. As PCNA fulfils a multifunctional role its expression may be an unreliable indicator of proliferation in benign tumours. The degree of tumour excision remains the best prognostic indicator while p53 is the main predictor of abnormal karyotype. Karyotype is not however, related to prognosis. Incompletely excised tumours which expressed high levels of p53 and p21 did not recur. It is suggested that this is indicative of a fully functional p53-mediated DNA damage response mechanism. Rather than contributing to tumour progression, p53 is fulfilling its role as guardian of the genome in benign meningiomas. This study shows that induction of senescence may be an important tumour suppressor mechanism in benign tumours.     

Experimental and empirical approaches in the study of aging

Two approaches to the study of aging are contrasted. The results and implications of the gene-by-gene, hypothetico-deductive molecular genetic approach are compared with studies engendered by uniqueempirical findings. The former hypothesis-testingapproach examines the changing phenotype that resultsfrom alterations of the genome and measures therelevance of a gene by the effectiveness with which italters life-span. Investigations of empiricaldemographic and physiological puzzles that have cometo light in aging studies, examine these phenomena forthe broader understanding they bring rather than theknowledge of specific causative genetic elements.While the former hypothesis testing method requirescaution in interpretation of results and conclusions,it has been highly informative. Studies ofempirical phenomena have necessarily progressed moreslowly, but have also yielded substantial gains. Both approaches have advanced the understanding ofthe aging process from distinctly different butcomplementary viewpoints.     

Autophagy inhibits the mesenchymal stem cell aging induced by D-galactose through ROS/JNK/p38 signalling

Autophagy and cellular senescence are two critical responses of mammalian cells to stress and may have a direct relationship given that they respond to the same set of stimuli, including oxidative stress, DNA damage, and telomere shortening. Mesenchymal stem cells (MSCs) have emerged as reliable cell sources for stem cell transplantation and are currently being tested in numerous clinical trials. However, the effects of autophagy on MSC senescence and corresponding mechanisms have not been fully evaluated. Several studies demonstrated that autophagy level increases in aging MSCs and the downregulation of autophagy can delay MSC senescence, which is inconsistent with most studies that showed autophagy could play a protective role in stem cell senescence. To further study the relationship between autophagy and MSC senescence and explore the effects and mechanisms of premodulated autophagy on MSC senescence, we induced the up- or down-regulation of autophagy by using rapamycin (Rapa) or 3-methyladenine, respectively, before MSC senescence induced by D-galactose (D-gal). Results showed that pretreatment with Rapa for 24 hours remarkably alleviated MSC aging induced by D-gal and inhibited ROS generation. p-Jun N-terminal kinases (JNK) and p-38 expression were also clearly decreased in the Rapa group. Moreover, the protective effect of Rapa on MSC senescence can be abolished by enhancing the level of ROS, and p38 inhibitor can reverse the promoting effect of H₂O₂ on MSC senescence. In summary, the present study indicates that autophagy plays a protective role in MSC senescence induced by D-gal, and ROS/JNK/p38 signalling plays an important mediating role in autophagy-delaying MSC senescence.     

岩藻黄素在振荡剪切应力致EPCs功能改变及衰老中的影响作用

目的探讨岩藻黄素(Fucoxanthin, FUCO)对振荡剪切应力作用下内皮祖细胞(Endothelial progenitor cells,EPCs)生物学功能及细胞衰老的影响作用。方法采用Flexcell STR-4000平行板流动系统模拟体内扰动流剪切应力(振荡剪切应力,Oscillatory shear stress,OSS,±4 dynes/cm2,1 Hz)并加载于EPCs;利用结晶紫染色法观察OSS作用后EPCs的形态学改变;应用Boyden小室、自发性细胞贴壁及Matrigel基质胶分别检测细胞迁移、黏附和体外血管形成能力的变化;采用Western blot检测促沉默信息调节因子1(Silent mating type information regulation 2 homolog-1,SIRT1)蛋白和β-半乳糖苷酶法检测细胞衰老程度的改变;通过Dihydroethidium(DHE)荧光探针法检测细胞内超氧化物阴离子。结果与静态培养组相比,OSS导致EPCs形态学发生明显改变,表现为细胞长宽比降低,细胞之间间距增加;而FUCO对OSS导致的EPCs形态学改变无显...     

MicroRNA-34a通过上调Cdc42和Rac1促进人晶状体上皮细胞衰老和凋亡

目的:观察MicroRNA-34a对人晶状体上皮细胞系SRA01/04衰老和凋亡的影响及作用机制。方法:qRT-PCR检测年龄相关性白内障(ARC)晶状体和透明晶状体上皮细胞中MicroRNA-34a表达水平,采用脂质体转染试剂盒将MicroRNA-34a mimics(过表达组)、MicroRNA-34a inhibitors(抑制组)和空脂质体(对照组)转染至SRA01/04细胞,qRT-PCR检测MicroRNA-34a的表达量;采用β-半乳糖苷酸(SA-β-gal)染色检测转染后细胞的衰老情况。Annexin V-FITC/PI双染色流式细胞仪检测MicroRNA-34a对人晶状体细胞系SRA01/04细胞凋亡的影响;蛋白免疫印迹检测Cdc42、Rac1蛋白的表达。结果:透明晶状体前囊膜组织中MicroRNA-34a的表达量显著低于ARC晶状体前囊膜组织(P<0.05);MicroRNA-34a过表达组、对照组、MicroRNA-34a抑制组SA-β-gal阳性率分别为(87.56±2.34)%、(12.22±2.74)%、(3.45±0.45)%。MicroRNA-34a过表达组明显高于对照组,而MicroRNA-34a抑制组SA-β-gal阳性率明显低于对照组(P<0.05);MicroRNA-34a抑制组、对照组和MicroRNA-34a过表达组的细胞凋亡率分别为(5.87±1.22)%、(12.26±2.14)%、(29.45±3.12)%,MicroRNA-34a抑制组细胞凋亡率明显低于对照组,而MicroRNA-34a过表达组细胞凋亡率明显高于对照组(P<0.05);MicroRNA-34a过表达组中Cdc42和Rac1的表达明显高于对照组(P<0.05),MicroRNA-34a抑制组中Cdc42和Rac1的表达明显低于对照组(P<0.05)。结论:MicroRNA-34a可能通过上调Cdc42和Rac1促进人晶状体上皮细胞衰老和凋亡。     

Doxorubicin‐induced normal breast epithelial cellular aging and its related breast cancer growth through mitochondrial autophagy and oxidative stress mitigated by ginsenoside Rh2

Clinical dose of doxorubicin (100 nM) induced cellular senescence and various secretory phenotypes in breast cancer and normal epithelial cells. Herein, we reported the detailed mechanism underlying ginsenoside Rh2‐mediated NF‐κB inhibition, and mitophagy promotion were evaluated by antibody array assay, western blotting analysis, and immunocytostaining. Ginsenoside Rh2 suppressed the protein levels of TRAF6, p62, phosphorylated IKK, and IκB, which consequently inactivated NF‐κB activity. Rh2‐mediated secretory phenotype was delineated by the suppressed IL‐8 secretion. Senescent epithelial cells showed increased level of reactive oxygen species (ROS), which was significantly abrogated by Rh2, with upregulation on SIRT 3 and SIRT 5 and subsequent increase in SOD1 and SOD2. Rh2 remarkably favored mitophagy by the increased expressions of PINK1 and Parkin and decreased level of PGC‐1α. A decreased secretion of IL‐8 challenged by mitophagy inhibitor Mdivi‐1 with an NF‐κB luciferase system was confirmed. Importantly, secretory senescent epithelial cells promoted the breast cancer (MCF‐7) proliferation while decreased the survival of normal epithelial cells demonstrated by co‐culture system, which was remarkably alleviated by ginsenoside Rh2 treatment. These data included ginsenoside Rh2 regulated ROS and mitochondrial autophagy, which were in large part attributed to secretory phenotype of senescent breast epithelial cells induced by doxorubicin. These findings also suggested that ginsenoside Rh2 is a potential treatment candidate for the attenuation of aging related disease.     

虫草真菌棒束孢霉的营养成分及其延缓衰老的作用

本文对虫草真菌棒束孢霉固体发酵物的营养成分进行了测定，表明该物含有较丰富的蛋白质、糖类、矿物质，并含有一定量的甘露醇、麦角甾醇；氨基酸含量也较高。超氧化牧歧化酶活性达３４０Ｕ／ｇ干重，并含有较高活力的蛋白酶、糖化酶及磷酸脂酶。急性毒理实验证明其为无素物质。用棒束孢霉菌丝体醇水抽提物灌胃小鼠，表明它能显著提高各脏器ＳＯＤ和肝脏过氧化氢酶活力，降低脏器中Ｂ型单胺氧化酶活力及作为脂质过氧化产物的丙二醛含量，因而可能具有延缓衰老功能。是一个较好的虫草人工代用品，具有广泛的应用前景     

茶多酚调节STAT3/miR-126/端粒信号通路活性延缓高糖诱导的人肾小球系膜细胞衰老

探讨茶多酚(tea polyphenols,TP)在体外高糖环境下延缓人肾小球系膜细胞(human glomerular mesangial cells,HGMCs)衰老的作用及可能的机制。在体外培养HGMCs,分为正常组(normal group,N,5.5 mmol·L^-1葡萄糖)、甘露醇组(mannitol group,MNT,5.5 mmol·L^-1葡萄糖+24.5 mmol·L^-1甘露醇)、高糖组(high dose of D-glucose group,HG,30 mmol·L^-1葡萄糖)、低剂量TP组(low dose of TP group,L-TP,30 mmol·L^-1葡萄糖+5 mg·L^-1 TP)及高剂量TP组(high dose of TP group,H-TP,30 mmol·L^-1葡萄糖+20 mg·L^-1 TP),分别在37℃,5%CO2条件下培养,干预72 h后,首先观察TP对HGMCs形态的影响;其次,检测细胞周期、衰老相关半乳糖苷酶(senescence-associated-β-galactosidase,SA-β-gal)染色阳性率、端粒长度;最后,检测p53-p21-Rb信号通路中关键信号分子p53,p21,Rb的蛋白表达水平及p-STAT3,miR-126的表达水平。结果表明,高糖能诱导HGMCs衰老,不仅表现为细胞周期阻滞于G1期、SA-β-gal染色阳性率升高、端粒长度缩短,还表现为p53,p21,Rb蛋白表达水平升高和p53-p21-Rb信号通路激活。L-TP能延缓HGMCs衰老,不仅表现为HGMCs细胞周期G1期阻滞的改善、SA-β-gal染色阳性率的下降、端粒长度的延长,还表现为p53,p21,Rb蛋白表达水平的下降,端粒-p53-p21-Rb信号通路活性的抑制。此外,高糖诱导HGMCs p-STAT3表达水平上调、miR-126表达水平下调,而L-TP可使这些变化得到改善。总之,高糖能激活端粒-p53-p21-Rb信号通路而诱导HGMCs衰老;L-TP能调节STAT3/miR-126表达水平,抑制端粒-p53-p21-Rb信号通路活性而延缓高糖诱导的HGMCs衰老。这些发现为临床上防治糖尿病肾病相关的肾脏细胞衰老提供了有效的干预措施。     

肾虚衰老理论研究的新思路

在中医学中,肾虚衰老一直占主导地位,而生命科学研究则表明机体生长、发育与衰老的基础是以细胞周期为核心的细胞增殖、分化与衰老等生命活动,两者之间必然有着某种本质的联系,将肾虚衰老、肾藏精、肾为先天之本理论与细胞基本生命活动之一的"细胞衰老"结合研究,可进一步揭示肾虚衰老理论的本质以及补肾防衰老的分子机制,同时可从另一个角度揭示目前尚未知的中医肾本质,从而深化中医学肾为先天之本理论.     

当归多糖诱导人白血病干细胞衰老与调控端粒系统机制的研究

目的探讨当归多糖(ASP)调控人CD34+CD38-骨髓白血病干细胞(LSC)衰老的端粒与端粒酶机制。方法免疫磁性分选人骨髓CD34+CD38-LSC;CCK-8检测ASP对CD34+CD38-LSC增殖抑制能力;衰老相关β半乳糖苷酶(SA-β-Gal)染色检测细胞衰老情况;混合集落培养(CFU-Mix)检测细胞增殖能力;荧光定量RT-PCR检测端粒酶基因TERT变化;TRAP-PCR检测细胞端粒酶活性;Southern blotting检测细胞端粒长度变化。结果免疫磁性分选后人骨髓CD34+CD38-LSC纯度达(91.15±2.41)%,相差显微镜观察显示细胞形态饱满,透明度高,折光性强。ASP体外诱导CD34+CD38-LSC 48 h,能有效抑制其增殖且呈浓度依赖性(P<0.05),集落形成能力下降(P<0.01)。40μg/mL ASP作用CD34+CD38-LSC 48 h,SA-β-Gal染色阳性细胞率明显升高(P<0.01);CD34+CD38-LSC端粒酶基因TERT表达水平下降(P<0.05);端粒酶活性下降(P<0.05);端粒长度缩短(P<0.05)。结论 ASP在体外可能通过调控细胞端粒系统诱导人骨髓CD34+CD38-LSC衰老。