Dose rectification of an imbalance between DPP4 and GLP‐1 ameliorates chronic stress‐related vascular aging and atherosclerosis?

Exposure to psychosocial stress is a risk factor for cardiovascular disease, including vascular aging and regeneration. Dipeptidyl peptidase‐4 (DPP‐4) exerts many physiological and pharmacological functions by regulating its extremely abundant substrates [eg., glucagon‐like peptide‐1 (GLP‐1), stromal cell‐derived factor‐1α/C‐X‐C chemokine receptor type‐4, etc.]. Over the past decade, emerging data has revealed unexpected roles for DPP‐4 and GLP‐1 in intracellular signaling, oxidative stress production, lipid metabolism, cell apoptosis, immune activation, insulin resistance, and inflammation. This mini review focuses on recent findings in this field, highlighting an imbalance between DPP4 and GLP‐1 as a potential therapeutic target in the management of vascular aging and atherosclerosis in animals under experimental stress conditions.     

作物秸秆对黄瓜衰老中根系活力和叶片氮代谢的影响

以‘津优4号’黄瓜为试验材料,研究施用不同作物秸秆对衰老过程中黄瓜根系活力和叶片氮代谢关键酶、叶片氮素含量及可溶性蛋白含量等影响。结果表明,与对照相比,作物秸秆还田不仅显著提高了黄瓜的根系活力、叶绿素含量和叶片氮代谢关键酶硝酸还原酶、谷氨酰胺合成酶、谷氨酸合成酶的活性,降低了谷氨酸脱氢酶活性,而且还降低了叶片铵态氮的含量(15.6 μg·g^-1),提高了叶片硝态氮、可溶性蛋白及游离氨基酸的含量,有效地保持较高的氮代谢水平,延缓了黄瓜的衰老。其中施用玉米秸秆效果最好,黄瓜的根系活力、硝酸还原酶活性、可溶性蛋白含量分别比对照提高了23.4%、33.3%、18.7%,其次为花生秸秆,硝酸还原酶活性比对照提高了10.8%,施用稻壳效果不明显。     

Protective effect of curcumin (Curcuma longa) against d-galactose-induced senescence in mice

Brain senescence plays an important role in cognitive dysfunction and neurodegenerative disorders. Curcumin was reported to have beneficial effect against several neurodegenerative disorders including Alzheimer's disease. Therefore, the present study was conducted in order to explore the possible role of curcumin against d-galactose-induced cognitive dysfunction, oxidative damage, and mitochondrial dysfunction in mice. Chronic administration of d-galactose for 6 weeks significantly impaired cognitive function (both in Morris water maze and elevated plus maze), locomotor activity, oxidative defense (raised lipid peroxidation, nitrite concentration, depletion of reduced glutathione and catalase activity), and mitochondrial enzyme complex activities (I, II, and III) as compared to vehicle treated group. Curcumin (15 and 30 mg/kg) and galantamine (5 mg/kg) treatment for 6 weeks significantly improved cognitive tasks, locomotor activity, oxidative defense, and restored mitochondrial enzyme complex activity as compared to control (d-galactose). Chronic d-galactose treatment also significantly increased acetylcholine esterase activity that was attenuated by curcumin (15 and 30 mg/kg) and galantamine (5 mg/kg) treatment. In conclusion, the present study highlights the therapeutic potential of curcumin against d-galactose induced senescence in mice.     

人参皂苷Rg1延缓造血干细胞衰老与 p16INK4a表达关系的研究

目的:探讨人参皂苷单体Rg1延缓造血干细胞(HSC)衰老与p16INK4a的表达调控关系,为寻找延缓HSC衰老途径提供理论和实验依据.方法:免疫磁性分选法分离纯化Sca-1+HSC后分组.对照组常规培养;衰老组运用三丁基过氧化氢(t-BHP)复制衰老模型;Rg1组在对照组基础上加入10μmol·L-1Rg1共培养;Rg1延缓衰老组给予10μmol·L-1Rg1预处理后,复制衰老模型;Rg1治疗衰老组,衰老模型复制后,给予10μmol·L-1Rg1抗衰老处理.衰老相关β半乳糖苷酶(SA-β-gal)细胞化学染色、流式细胞术分析细胞周期和造血祖细胞混合集落(CFU-Mix)培养确定Rg1延缓或治疗Sca-1+HSC衰老生物学作用.RT-PCR及Western blotting检测衰老相关基因pl6INK4amRNA及蛋白的表达.结果:Rg1延缓衰老组,Rg1治疗衰老组与衰老组相比,SA-β-gal染色阳性细胞百分比降低,G1期细胞比例下降,生成造血祖细胞混合集落数增加,p16INK4amRNA及蛋白的表达下降;Rg1延缓衰老组的SA-β-gal染色阳性细胞百分比、G1期比例、pl6INK4amRNA及蛋白的表达均低于Rg1治疗衰老组,形成造血祖细胞混合集落数高于Rg1治疗衰老组.结论:Rg1具有延缓和治疗Sca-1+HSC衰老的作用,Rg1延缓衰老比治疗衰老效果更好.Rg1可能通过调控p16INK4a的表达发挥其对抗t-BHP诱导的Sca-1+HSC衰老的作用.     

人之衰老肾为其本——试论肾虚衰老说

衰老是人类生命过程的必然规律,肾中精气的盛衰与衰老发生的早迟息息相关,且贯穿于整个衰老的过程,肾虚与衰老的关系早在《黄帝内经》中即有所论述。不仅从古代文献中进行引证,也从肾虚致衰的现代医学理论基础加以证明,认为人体衰老的根本是肾中精气发生了变化,只有补肾固精,扶其根本才能最大限度地延长人类的平均寿命,以至渐臻天年。     

不同月龄大鼠血清IL-2、IL-4、IL-6含量比较

目的：比较不同月龄大鼠免疫功能及抗氧化能力的差异。方法：选择15、25月龄健康雄性SD大鼠各10只，以3月龄青年鼠10只为对照组。采用放免法测定血清白细胞介素-2(IL-2)、白细胞介素-4(IL-4)、白细胞介素-6(IL-6)含量，并计算大鼠胸腺体重指数；采用化学法检测血清超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)活力，丙二醛(MDA)含量。结果：衰老大鼠胸腺体重指数及IL-2、IL-4明显下降，IL-6水平升高SOD、GSH-PX活力下降，MDA含量增高，并且变化与月龄有关。结论：不同月龄大鼠衰老状况各有特点，不同年龄阶段应采用不同方法延缓衰老。     

六味地黄汤对快速老化模型小鼠下丘脑-垂体-卵巢轴的调节作用及机理研究

目的 研究快速老化模型小鼠(senescence accelerated mice,SAM)增龄过程中下丘脑一垂体一卵巢(HPO)轴功能的变化及六味地黄汤(LW)的调节作用。方法采用阴道涂片法确定动物的动情周期;放射免疫分析法检测血清雌二醇(E2)水平及下丘脑β-内啡肽(β-EP)和P物质(SP)含量;蛋白免疫印迹法(westemb lotting法)检测垂体促黄体生成素(LH)、垂体及卵巢雌激素受体a(ERa)水平。结果在增龄过程中SAM快速老化亚系SAM-prone／8(SAMP8)的动情周期和动情间期均较同龄抗快速老化系SAM-resis-tance／1(SAMRl)明显延长,血清E2水平显著降低、垂体LH水平显著升高,下丘脑β-EP含量随增龄逐渐下降,SP含量一过性升高后又下降,卵巢ERa表达量明显低下。LW能显著缩短SAMP8动情间期,增加卵巢重量,升高血清E2水平,明显降低垂体LH水平;并能升高下丘脑β-EP含量,提高卵巢ERa的表达量,但却明显降低下丘脑SP含量。口服雌激素能显著提高SAMP8血清E2水平,降低垂体LH水平,升高下丘脑β-EP及SP含量,并增加垂体ERa表达量,但明显降低卵巢重量及ERa水平。结论SAMP8在衰老过程中所表现的进行性HPO轴功能紊乱与下丘脑肽类神经递质含量及卵巢ERa水平的变化具有密切关系。LW对SAMP8 HPO轴功能紊乱具有改善或调节作用。     

EWS/FLI1 suppresses retinoblastoma protein function and senescence in Ewing's sarcoma cells

Ewing's Family Tumors (EFTs) most commonly harbor a specific t(11;22) translocation that generates the EWS/FLI1 fusion protein responsible for malignant transformation. Many potential downstream targets of EWS/FLI1 have been identified but a detailed mechanism by which the fusion protein brings about transformation remains unknown. In this report, we show that depletion of EWS/FLI1 in Ewing's cell lines results in a senescence phenotype, a marked increase in expression of the G1/S regulatory proteins p27^kip1 and p57^kip2, and a significant decrease in cyclin D1 and CDK2. We also demonstrate for the first time, to our knowledge, that knockdown of EWS/FLI1 leads to hypophosphorylation and functional activation of the retinoblastoma (pRb) family of proteins. Consistent with activation of the pRb proteins, E2F‐responsive genes such as cyclin A are repressed in EWS/FLI1‐depleted cells. Together, these results support the role of EWS/LI1 as an inhibitor of cellular senescence and implicate the retinoblastoma family of proteins as key mediators of this inhibition. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:886–893, 2008     

Increased electrotonic coupling in aged rat hippocampus: a possible mechanism for cellular excitability changes

The effects of aging on the intercellular transfer of the low molecular weight fluorescent dye 5,6-carboxyfluorescein was studied in subfields fascia dentata, CA1, and CA3 of rat hippocampal slices maintained in vitro. All three areas exhibited a statistically significant increase in dye coupling with age. The increased dye coupling was accompanied by an apparent increase in postsynaptic excitability as assessed by the ratio of the population spike to EPSP components of the extracellulary recorded field potential. The possibility that artifactual dye coupling due to cell fusion contributed significantly to these results was ruled out by the demonstrations that a high molecular weight, dextran-coupled fluorescein compound did not produce multiple fills and that dye coupling with carboxyfluorescein could be prevented by prior intracellular loading with Ca++, a procedure that decouples gap junctions in other tissue. The increase in extent of electrical coupling suggested by these data may largely account for the apparent increase in cellular excitability of this tissue with age and may reflect the mechanism by which the senescent hippocampus compensates for the loss of afferent input during the course of normal aging. The additional possibility is raised that increased electrical coupling may reflect a mechanism for permanent associative storage of information in this system.     

Influence of in vitro biomimicked stem cell ‘niche’ for regulation of proliferation and differentiation of human bone marrow‐derived mesenchymal stem cells to myocardial phenotypes: serum starvation without aid of chemical agents and prevention of spontaneous stem cell transformation enhanced by the matrix environment

Niche appears important for preventing the spontaneous differentiation or senescence that cells undergo during in vitro expansion. In the present study, it was revealed that human bone marrow‐derived mesenchymal stem cells (hBM‐MSCs) undergo senescence‐related differentiation into the myocardial lineage in vitro without any induction treatment. This phenomenon occurred over the whole population of MCSs, much different from conventional differentiation with limited frequency of occurrence, and was accompanied by a change of morphology into large, flat cells with impeded proliferation, which are the representative indications of MSC senescence. By culturing MSCs under several culture conditions, it was determined that induction treatment with 5‐azacytidine was not associated with the phenomenon, but the serum‐starvation condition, under which proliferation is severely hampered, caused senescence progression and upregulation of cardiac markers. Nevertheless, MSCs gradually developed a myocardial phenotype under normal culture conditions over a prolonged culture period and heterogeneous populations were formed. In perspectives of clinical applications, this must be prevented for fair and consistent outcomes. Hence, the biomimetic 'niche' was constituted for hBM‐MSCs by cultivating on a conventionally available extracellular matrix (ECM). Consequently, cells on ECM regained a spindle‐shape morphology, increased in proliferation rate by two‐fold and showed decreased expression of cardiac markers at both the mRNA and protein levels. In conclusion, the outcome indicates that progression of MSC senescence may occur via myocardial differentiation during in vitro polystyrene culture, and this can be overcome by employing appropriate ECM culture techniques. Copyright © 2013 John Wiley & Sons, Ltd.