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991.
992.
Telomere length homeostasis is achieved by a balance of telomere shortening caused by DNA replication and nucleolytic attack and telomere lengthening by telomerase. The importance of telomere length maintenance to human health is best illustrated by dyskeratosis congenita (DC), a disease of telomere shortening caused by mutations in telomerase subunits. DC patients suffer stem cell depletion and die of bone marrow stem cell failure. Recently a new class of particularly severe DC patients was found to harbor mutations in the shelterin subunit TIN2. The DC-TIN2 mutations were clustered in small domain of unknown function. In a recently published study we showed that the DC mutation cluster in TIN2 harbored a binding site for heterochromatin protein 1 (HP1) and, further, that HP1 binding to TIN2 was required for sister telomere cohesion in S phase and for telomere length maintenance by telomerase. We briefly review and discuss the implications of our findings in this Extra View and present some new data that may shed light on how sister telomere cohesion could influence telomere elongation by telomerase.Key words: telomeres, cohesion, telomerase, TIN2, dyskeratosis congenita 相似文献
993.
994.
Bañez-Coronel M Porta S Kagerbauer B Mateu-Huertas E Pantano L Ferrer I Guzmán M Estivill X Martí E 《PLoS genetics》2012,8(2):e1002481
Huntington's disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of ≈21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism. In both cases, the use of anti-miRs specific for sCAGs efficiently blocked the toxic effect, supporting a key role of sCAGs in HTT-mediated toxicity. Luciferase-reporter assays showed that expanded HTT silences the expression of CTG-containing genes that are down-regulated in HD. These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches. 相似文献
995.
Debora Franceschini Paola Del Porto Silvia Piconese Emanuele Trella Daniele Accapezzato Marino Paroli Stefania Morrone Enza Piccolella Enea Spada Alfonso Mele John Sidney Alessandro Sette Vincenzo Barnaba 《PLoS pathogens》2012,8(6)
Caspase-dependent cleavage of antigens associated with apoptotic cells plays a prominent role in the generation of CD8+ T cell responses in various infectious diseases. We found that the emergence of a large population of autoreactive CD8+ T effector cells specific for apoptotic T cell-associated self-epitopes exceeds the antiviral responses in patients with acute hepatitis C virus infection. Importantly, they endow mixed polyfunctional type-1, type-2 and type-17 responses and correlate with the chronic progression of infection. This evolution is related to the selection of autoreactive CD8+ T cells with higher T cell receptor avidity, whereas those with lower avidity undergo prompt contraction in patients who clear infection. These findings demonstrate a previously undescribed strict link between the emergence of high frequencies of mixed autoreactive CD8+ T cells producing a broad array of cytokines (IFN-γ, IL-17, IL-4, IL-2…) and the progression toward chronic disease in a human model of acute infection. 相似文献
996.
De Felice C Signorini C Durand T Ciccoli L Leoncini S D'Esposito M Filosa S Oger C Guy A Bultel-Poncé V Galano JM Pecorelli A De Felice L Valacchi G Hayek J 《Genes & nutrition》2012,7(3):447-458
Evidence of enhanced oxidative stress (O.S.) and lipid peroxidation has been reported in patients with Rett syndrome (RTT), a relatively rare neurodevelopmental disorder progressing in 4-stages, and mainly caused by loss-of-function mutations in the methyl-CpG-binding protein 2. No effective therapy for preventing or arresting the neurologic regression in the disease in its various clinical presentations is available. Based on our prior evidence of enhanced O.S. and lipid peroxidation in RTT patients, herein we tested the possible therapeutic effects of ω-3 polyunsaturated fatty acids (ω-3 PUFAs), known antioxidants with multiple effects, on the clinical symptoms and O.S. biomarkers in the earliest stage of RTT. A total of 20 patients in stage I were randomized (n = 10 subjects per arm) to either oral supplementation with ω-3 PUFAs-containing fish oil (DHA: 72.9 ± 8.1 mg/kg b.w./day; EPA: 117.1 ± 13.1 mg/kg b.w./day; total ω-3 PUFAs: 246.0 ± 27.5 mg/kg b.w./day) for 6 months or no treatment. Primary outcomes were potential changes in clinical symptoms, with secondary outcomes including variations for five O.S. markers in plasma and/or erythrocytes (nonprotein bound iron, F2-dihomo-isoprostanes, F3-isoprostanes, F4-neuroprostanes, and F2-isoprostanes). A significant reduction in the clinical severity (in particular, motor-related signs, nonverbal communication deficits, and breathing abnormalities) together with a significant decrease in all the examined O.S. markers was observed in the ω-3 PUFAs supplemented patients, whereas no significant changes were evidenced in the untreated group. For the first time, these findings strongly suggest that a dietary intervention in this genetic disease at an early stage of its natural history can lead to a partial clinical and biochemical rescue.
Electronic supplementary material
The online version of this article (doi:10.1007/s12263-012-0285-7) contains supplementary material, which is available to authorized users. 相似文献997.
Roman Thaler Silvia Spitzer Heidrun Karlic Klaus Klaushofer Franz Varga 《Epigenetics》2012,7(6):635-651
Artificial induction of active DNA demethylation appears to be a possible and useful strategy in molecular biology research and therapy development. Dimethyl sulfoxide (DMSO) was shown to cause phenotypic changes in embryonic stem cells altering the genome-wide DNA methylation profiles. Here we report that DMSO increases global and gene-specific DNA hydroxymethylation levels in pre-osteoblastic MC3T3-E1 cells. After 1 day, DMSO increased the expression of genes involved in DNA hydroxymethylation (TET) and nucleotide excision repair (GADD45) and decreased the expression of genes related to DNA methylation (Dnmt1, Dnmt3b, Hells). Already 12 hours after seeding, before first replication, DMSO increased the expression of the pro-apoptotic gene Fas and of the early osteoblastic factor Dlx5, which proved to be Tet1 dependent. At this time an increase of 5-methyl-cytosine hydroxylation (5-hmC) with a concomitant loss of methyl-cytosines on Fas and Dlx5 promoters as well as an increase in global 5-hmC and loss in global DNA methylation was observed. Time course-staining of nuclei suggested euchromatic localization of DMSO induced 5-hmC. As consequence of induced Fas expression, caspase 3/7 and 8 activities were increased indicating apoptosis. After 5 days, the effect of DMSO on promoter- and global methylation as well as on gene expression of Fas and Dlx5 and on caspases activities was reduced or reversed indicating down-regulation of apoptosis. At this time, up regulation of genes important for matrix synthesis suggests that DMSO via hydroxymethylation of the Fas promoter initially stimulates apoptosis in a subpopulation of the heterogeneous MC3T3-E1 cell line, leaving a cell population of extra-cellular matrix producing osteoblasts. 相似文献
998.
Corrochano S Renna M Tomas-Zapico C Brown SD Lucas JJ Rubinsztein DC Acevedo-Arozena A 《Autophagy》2012,8(3):431-432
Huntington and Parkinson diseases (HD and PD) are two major neurodegenerative disorders pathologically characterized by the accumulation of the aggregate-prone proteins mutant huntingtin (in HD) and α-synuclein (in PD). Mutant huntingtin is an autophagy substrate and autophagy modulators affect HD pathology both in vitro and in vivo. In vitro, α-synuclein levels are able to modulate autophagy: α-synuclein overexpression inhibits autophagy, whereas downregulation promotes autophagy. Here, we review our recent studies showing that α-synuclein levels modulate mutant huntingtin toxicity in mouse models. This phenotypic modification is accompanied by the in vivo modulation of autophagosome numbers in mouse brains from both control and HD mice expressing different levels of α-synuclein. 相似文献
999.
Traditionally regarded as stable through the entire lifespan, the intestinal microbiota has now emerged as an extremely plastic entity, capable of being reconfigured in response to different environmental factors. In a mutualistic context, these microbiome fluctuations allow the host to rapidly adjust its metabolic and immunologic performances in response to environmental changes. Several circumstances can disturb this homeostatic equilibrium, inducing the intestinal microbiota to shift from a mutualistic configuration to a disease-associated profile. A mechanistic comprehension of the dynamics involved in this process is needed to deal more rationally with the role of the human intestinal microbiota in health and disease. 相似文献
1000.
Gabrieli L. Parrilha Rafael P. Vieira Paula P. Campos Grácia Divina F. Silva Lucienir P. Duarte Silvia P. Andrade Heloisa Beraldo 《Biometals》2012,25(1):55-62
Complex [Bi(Lp)2]Cl was obtained with 4-hydroxy-3-(3-methylbut-2-enyl)naphthalene-1,2-dione, “lapachol” (HLp). Lapachol, [Bi(Lp)2]Cl and BiCl3 were evaluated in a murine model of inflammatory angiogenesis induced by subcutaneous implantation of polyether polyurethane
sponge discs. Intraperitoneal (i.p.) administration of lapachol or [Bi(Lp)2]Cl reduced the hemoglobin content in the implants suggesting that reduction of neo-vascularization was caused by lapachol.
In the per os treatment only [Bi(Lp)2]Cl decreased the hemoglobin content in the implants. Likewise, N-acetylglucosaminidase (NAG) activity decreased in the implants of the groups i.p. treated with lapachol and [Bi(Lp)2]Cl while in the per os treatment inhibition was observed only for [Bi(Lp)2]Cl. Histological analysis showed that the components of the fibro-vascular tissue (vascularization and inflammatory cell
population) were decreased in lapachol- and complex-treated groups. Our results suggest that both lapachol and [Bi(Lp)2]Cl exhibit anti-angiogenic and anti-inflammatory activities which have been attributed to the presence of the lapachol ligand.
However, coordination to bismuth(III) could be an interesting strategy for improvement of lapachol’s therapeutic properties. 相似文献