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ApoE telomere

Aarti Shah, Kelly Gray, Nichola Figg, Alison Finigan, Lakshi Starks, Martin Bennett
Background -Atherosclerotic plaques demonstrate extensive accumulation of oxidative DNA damage, predominantly as 8-oxoguanine (8oxoG) lesions. 8oxoG is repaired by base excision repair (BER) enzymes; however, the mechanisms regulating 8oxoG accumulation in vascular smooth muscle cells (VSMCs) and its effects on their function and in atherosclerosis are unknown. Methods -We studied levels of 8oxoG and its regulatory enzymes in human atherosclerosis, the mechanisms regulating 8oxoG repair and the BER enzyme 8oxoG DNA glycosylase I (OGG1) in VSMCs in vitro, and the effects of reducing 8oxoG in VSMCs in atherosclerosis in ApoE-/- mice...
April 11, 2018: Circulation
Gavin Richardson, Andrew Sage, Karim Bennaceur, Nayef Al Zhrany, Jose Coelho-Lima, Emily Dookun, Lilia Draganova, Gabriele Saretzki, David T Breault, Ziad Mallat, Ioakim Spyridopoulos
OBJECTIVE: Atherosclerosis is an age-related disease characterized by systemic oxidative stress and low-grade inflammation. The role of telomerase and telomere length in atherogenesis remains contentious. Short telomeres of peripheral leukocytes are predictive for coronary artery disease. Conversely, attenuated telomerase has been demonstrated to be protective for atherosclerosis. Hence, a potential causative role of telomerase in atherogenesis is critically debated. APPROACH AND RESULTS: In this study, we used multiple mouse models to investigate the regulation of telomerase under oxidative stress as well as its impact on atherogenesis in vitro and in vivo...
March 29, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Babitha Machireddy, Gurmannat Kalra, Subash Jonnalagadda, Kandalam Ramanujachary, Chun Wu
Human telomeric DNA G-quadruplex has been identified as a good therapeutic target in cancer treatment. G-quadruplex-specific ligands that stabilize the G-quadruplex have great potential to be developed as anticancer agents. Two crystal structures (an apo form of parallel stranded human telomeric G-quadruplex and its holo form in complex with BRACO19, a potent G-quadruplex ligand) have been solved, yet the binding mechanism and pathway remain elusive. In this study, we simulated the binding of a free BRACO19 molecule to the apo form of the G-quadruplex using the latest AMBER DNA (OL15) and ligand (GAFF2) force fields...
November 27, 2017: Journal of Chemical Information and Modeling
Lei Lv, Meng Ye, Rundan Duan, Kai Yuan, Jiaquan Chen, Wei Liang, Zhaoxiong Zhou, Lan Zhang
OBJECTIVE: Pin1 is prevalently overexpressed in human cancers and implicated to regulate cell growth and apoptosis. Thus far, however, no role for Pin1 has been described in modulating vascular smooth muscle cell (VSMC) senescence. METHODS: Immunohistochemistry and Western blotting were used to assess Pin1 protein level in human normal and atherosclerotic tissues. β-galactosidase staining, cumulative population doubling level, telomerase activity, and relative telomere length measurement were used to confirm VSMC senescence...
October 3, 2017: Journal of Vascular Surgery
Daniela Scarabino, Elisabetta Broggio, Giuseppe Gambina, Rosa Maria Corbo
Numerous studies have reported an association between shortened leukocyte telomere length (LTL) and increased risk of Alzheimer's disease (AD). In this study we investigated the relationship between LTL and AD development, including in the analysis patients with amnestic mild cognitive impairment (aMCI), a clinical entity considered prodromal of AD. LTL (T/S ratio) was measured in patients with AD (n=61) or aMCI (n=46), and compared with LTL of age-matched controls (n=56). Significant LTL differences were observed between controls, aMCI and AD patients (p<0...
August 19, 2017: Experimental Gerontology
Allan S Pires, William F Porto, Octavio L Franco, Sérgio A Alencar
ApoE3 is the major chylomicron apolipoprotein, binding in a specific liver peripheral cell receptor, allowing transport and normal catabolism of triglyceride-rich lipoprotein constituents. Point mutations in ApoE3 have been associated with Alzheimer's disease, type III hyperlipoproteinemia, atherosclerosis, telomere shortening and impaired cognitive function. Here, we evaluate the impact of missense SNPs in APOE retrieved from dbSNP through 16 computational prediction tools, and further evaluate the structural impact of convergent deleterious changes using 100 ns molecular dynamics simulations...
May 30, 2017: Scientific Reports
S Hägg, Y Zhan, R Karlsson, L Gerritsen, A Ploner, S J van der Lee, L Broer, J Deelen, R E Marioni, A Wong, A Lundquist, G Zhu, N K Hansell, E Sillanpää, I O Fedko, N A Amin, M Beekman, A J M de Craen, S Degerman, S E Harris, K-J Kan, C M Martin-Ruiz, G W Montgomery, A N Adolfsson, C A Reynolds, N J Samani, H E D Suchiman, A Viljanen, T von Zglinicki, M J Wright, J-J Hottenga, D I Boomsma, T Rantanen, J A Kaprio, D R Nyholt, N G Martin, L Nyberg, R Adolfsson, D Kuh, J M Starr, I J Deary, P E Slagboom, C M van Duijn, V Codd, N L Pedersen
The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP)...
April 18, 2017: Translational Psychiatry
Yasumichi Arai, Takashi Sasaki, Nobuyoshi Hirose
The scope and purpose of this review was to summarize the aims, methods, findings, and future of centenarian and (semi)-supercentenarian studies in Japan, particularly those from our own interdisciplinary laboratory. Medically, approximately 97% of centenarians contract chronic diseases including hypertension and gastrointestinal disease; however, they present with few cardiovascular risk factors. The low prevalence of diabetes mellitus and carotid atherosclerotic plaques is peculiarities of centenarians, which could be associated with high adiponectin levels...
July 2017: Mechanisms of Ageing and Development
Merav Darash-Yahana, Yair Pozniak, Mingyang Lu, Yang-Sung Sohn, Ola Karmi, Sagi Tamir, Fang Bai, Luhua Song, Patricia A Jennings, Eli Pikarsky, Tamar Geiger, José N Onuchic, Ron Mittler, Rachel Nechushtai
Iron-sulfur (Fe-S) proteins are thought to play an important role in cancer cells mediating redox reactions, DNA replication, and telomere maintenance. Nutrient-deprivation autophagy factor-1 (NAF-1) is a 2Fe-2S protein associated with the progression of multiple cancer types. It is unique among Fe-S proteins because of its 3Cys-1His cluster coordination structure that allows it to be relatively stable, as well as to transfer its clusters to apo-acceptor proteins. Here, we report that overexpression of NAF-1 in xenograft breast cancer tumors results in a dramatic augmentation in tumor size and aggressiveness and that NAF-1 overexpression enhances the tolerance of cancer cells to oxidative stress...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
H Hoffman, E Skordalakes
Telomeres are nucleoprotein complexes that maintain the ends of our chromosomes thus providing genomic stability. Telomerase is a ribonucleoprotein reverse transcriptase that replicates the short tandem repeats of DNA known as telomeres. The telomeric DNA is specifically associated with two major complexes, the shelterin and CST complexes both of which are involved in telomere length regulation and maintenance along with telomerase. Obtaining structural information on these nucleoprotein complexes has been a major bottleneck in fully understanding the mechanism of action of telomeric nucleoproteins for over two decades...
2016: Methods in Enzymology
Mengyuan Liu, Ya Ruth Huo, Junwei Wang, Change Wang, Shuling Liu, Shuai Liu, Jinhuan Wang, Yong Ji
BACKGROUND AND AIMS: Sporadic Alzheimer's Disease (AD) is considered an age-related disease, and telomere length has been shown to decrease with age in animal and human studies. Shortening of telomere length has also been reported to beis associated with numerous neurodegenerative diseases, including AD. The aim of this study is to confirm and further elucidate the relationship between peripheral telomere length and Alzheimer's disease, cognitive function, and duration of Alzheimer's disease...
May 2016: Annals of Clinical and Laboratory Science
Gustav Nilsonne, Sandra Tamm, Kristoffer N T Månsson, Torbjörn Åkerstedt, Mats Lekander
Leukocyte telomere length has been shown to correlate to hippocampus volume, but effect estimates differ in magnitude and are not uniformly positive. This study aimed primarily to investigate the relationship between leukocyte telomere length and hippocampus gray matter volume by meta-analysis and secondarily to investigate possible effect moderators. Five studies were included with a total of 2107 participants, of which 1960 were contributed by one single influential study. A random-effects meta-analysis estimated the effect to r = 0...
2015: F1000Research
C Perez-Ternero, M D Herrera, U Laufs, M Alvarez de Sotomayor, C Werner
PURPOSE: Atherosclerosis is associated with reduced mononuclear cell (MNC) telomere length, and senescent cells have been detected in atherosclerotic plaques. Rice bran is a source of γ-oryzanol, phytosterols and tocols with potential lipid-lowering, antioxidant and anti-inflammatory activities. Here, we tested the hypothesis that rice bran enzymatic extract (RBEE) impacts on apoptosis, telomere length and atherogenesis in mice. METHODS: Seven-week-old male ApoE-/- mice were fed high-fat diet (HFD) or isocaloric HFD supplemented with 5 % (w/w) RBEE for 23 weeks...
February 2017: European Journal of Nutrition
Julie Wang, Anna K Uryga, Johannes Reinhold, Nichola Figg, Lauren Baker, Alison Finigan, Kelly Gray, Sheetal Kumar, Murray Clarke, Martin Bennett
BACKGROUND: Although vascular smooth muscle cell (VSMC) proliferation is implicated in atherogenesis, VSMCs in advanced plaques and cultured from plaques show evidence of VSMC senescence and DNA damage. In particular, plaque VSMCs show shortening of telomeres, which can directly induce senescence. Senescence can have multiple effects on plaque development and morphology; however, the consequences of VSMC senescence or the mechanisms underlying VSMC senescence in atherosclerosis are mostly unknown...
November 17, 2015: Circulation
Jesse I DuPont, Kate L Henderson, Amanda Metz, Vu H Le, Joseph P Emerson, Edwin A Lewis
BACKGROUND: The human telomere contains tandem repeat of (TTAGG) capable of forming a higher order DNA structure known as G-quadruplex. Porphyrin molecules such as TMPyP4 bind and stabilize G-quadruplex structure. METHODS: Isothermal titration calorimetry (ITC), circular dichroism (CD), and mass spectroscopy (ESI/MS), were used to investigate the interactions between TMPyP4 and the Co(III), Ni(II), Cu(II), and Zn(II) complexes of TMPyP4 (e.g. Co(III)-TMPyP4) and a model human telomere G-quadruplex (hTel22) at or near physiologic ionic strength ([Na(+)] or [K(+)]≈0...
May 2016: Biochimica et Biophysica Acta
J Polettini, E H Dutta, F Behnia, G R Saade, M R Torloni, R Menon
BACKGROUND: Many adverse pregnancy outcomes (APOs), including spontaneous preterm birth (PTB), are associated with placental dysfunction. Recent clinical and experimental evidences suggest that premature aging of the placenta may be involved in these events. Although placental aging is a well-known concept, the mechanisms of aging during normal pregnancy and premature aging in APOs are still unclear. This review was conducted to assess the knowledge on placental aging related biochemical changes leading to placental dysfunction in PTB and/or preterm premature rupture of membranes (pPROM)...
September 2015: Placenta
Jasmine Nettiksimmons, Hilsa Ayonayon, Tamara Harris, Caroline Phillips, Caterina Rosano, Suzanne Satterfield, Kristine Yaffe
OBJECTIVE: We sought to develop and validate a risk index for prospective cognitive decline in older adults based on blood-derived markers. METHODS: The index was based on 8 markers that have been previously associated with cognitive aging: APOE genotype, plasma β-amyloid 42/40 ratio, telomere length, cystatin C, glucose, C-reactive protein, interleukin-6, and albumin. The outcome was person-specific cognitive slopes (Modified Mini-Mental State Examination) from 11 years of follow-up...
February 17, 2015: Neurology
Grégoria Kalpouzos, Debora Rizzuto, Lina Keller, Johan Fastbom, Giola Santoni, Sara Angleman, Caroline Graff, Lars Bäckman, Laura Fratiglioni
Telomere length has been associated with longevity. As telomere length is partly determined by the human telomerase reverse transcriptase (hTERT), we investigated the association between an hTERT polymorphism located in its promoter region ((-) (1327)T/C) and longevity in two cohorts of older adults. Participants from the Kungsholmen project (KP; n = 1,205) and the Swedish National study of Aging and Care in Kungsholmen (SNAC-K; n = 2,764) were followed for an average period of 7.5 years. The main outcomes were hazard ratios (HR) of mortality and median age at death...
February 2016: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Kevin S King, Julia Kozlitina, Roger N Rosenberg, Ronald M Peshock, Roderick W McColl, Christine K Garcia
IMPORTANCE: Telomere length has been associated with dementia and psychological stress, but its relationship with human brain size is unknown. OBJECTIVE: To determine if peripheral blood telomere length is associated with brain volume. DESIGN, SETTING, AND PARTICIPANTS: Peripheral blood leukocyte telomere length and brain volumes were measured for 1960 individuals in the Dallas Heart Study, a population-based, probability sample of Dallas County, Texas, residents, with a median (25th-75th percentile) age of 50 (42-58) years...
October 2014: JAMA Neurology
Guodong Tie, Katharine E Messina, Jinglian Yan, Julia A Messina, Louis M Messina
BACKGROUND: Clinical studies suggest that hypercholesterolemia may cause ageing in hematopoietic stem cells (HSCs) because ageing-associated alterations were found in peripheral blood cells and their bone marrow residing precursors in patients with advanced atherosclerosis. We hypothesized that hypercholesterolemia induces oxidant stress in hematopoietic stems cells that accelerates their ageing. METHODS AND RESULTS: Here we show that HSCs from ApoE(-/-) mice, as well as HSCs from C57Bl/6 mice fed a high cholesterol diet (HCD) accumulated oxLDL and had greater ROS levels...
January 27, 2014: Journal of the American Heart Association
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