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Andreas Zietzer, Eva Elina Buschmann, Doreen Janke, Lulu Li, Michèle Brix, Heike Meyborg, Philipp Stawowy, Constantin Jungk, Ivo Buschmann, Philipp Hillmeister
AIM: Physical activity is a potent way to impede vascular aging. However, patients who suffer from peripheral artery disease (PAD) are often unable to exercise adequately. For those patients, we have developed individual shear rate therapy (ISRT), which is an adaptation of external counterpulsation and enhances endovascular fluid shear stress to increase collateral growth (arteriogenesis). To evaluate the effects of physical exercise and ISRT on the telomere biology of peripheral blood mononuclear cells (PBMCs), we conducted two clinical trials...
October 22, 2016: Acta Physiologica
Nathaniel J Robinson, William P Schiemann
Despite significant clinical advancements, cancer remains a leading cause of mortality throughout the world due largely to the process of metastasis and the dissemination of cancer cells from their primary tumor of origin to distant secondary sites. The clinical burden imposed by metastasis is further compounded by a paucity of information regarding the factors that mediate metastatic progression. Linear chromosomes are capped by structures known as telomeres, which dictate cellular lifespan in humans by shortening progressively during successive cell divisions...
October 18, 2016: Biochimica et Biophysica Acta
Brody Holohan, Wanil Kim, Tsung-Po Lai, Hirotoshi Hoshiyama, Ning Zhang, Anas M Alazami, Woodring E Wright, M Stephen Meyn, Fowzan S Alkuraya, Jerry W Shay
BACKGROUND: Loss of function in genes required for telomere maintenance result in disorders known as telomeropathies, which are characterized by a pattern of symptoms including generalized and specific lymphocytopenias as well as very short telomere length and disease anticipation. METHODS: Because human LARP7 is the most likely ortholog of the Tetrahymena p65 protein, which is required for telomerase activity in that organism, we investigated the effects of LARP7 silencing in human cells as well as in two distinct families with Alazami syndrome (loss of function of LARP7)...
October 17, 2016: BMC Genomics
C Piñol-Felis, T Fernández-Marcelo, J Viñas-Salas, C Valls-Bautista
Colorectal cancer (CRC) is the third most common cancer worldwide. Our aim is to describe the state of the art about the role of telomeres and telomerase in the clinical management of CRC and its potential utility as prognostic and diagnostic biomarkers and targets of new treatments. Telomere length could be a new diagnostic marker as an anomalous behavior is observed in peripheral blood cells when CRC patients and healthy people are compared. Moreover, telomeres and telomerase may be used as diagnostic markers considering that universal changes appear along the CRC process...
October 19, 2016: Clinical & Translational Oncology
Mi-Sun Kwon, Jaewon Min, Hee-Yeon Jeon, Kwangwoo Hwang, Chuna Kim, Junho Lee, Je-Gun Joung, Woong-Yang Park, Hyunsook Lee
BRCA2 is a multifunctional tumor suppressor involved in homologous recombination (HR), mitotic checkpoint regulation, and telomere homeostasis. Absence of Brca2 in mice results in progressive shortening of telomeres and senescence, yet cells are prone to neoplastic transformation with elongated telomeres, suggesting that BRCA2 has positive and negative effects on telomere length regulation along the path to tumorigenesis. Using Caenorhabditis elegans as a model, we show here that depletion of BRC-2, an ortholog of BRCA2, paradoxically delays senescence in telomerase-deficient mutant worms...
October 2016: FEBS Open Bio
Mitsuhiro Machitani, Fuminori Sakurai, Keisaku Wakabayashi, Masashi Tachibana, Toshiyoshi Fujiwara, Hiroyuki Mizuguchi
Oncolytic viruses have been receiving much attention as potential agents for cancer treatment. Among the various types of oncolytic viruses, the telomerase-specific replication-competent adenovirus (TRAD), which carries the tumor-specific promoter-driven E1 gene expression cassette, exhibits efficient antitumor effects. The development of a novel TRAD that shows higher replication efficiency and antitumor activity would be highly beneficial for safer and more efficient cancer therapy. We recently demonstrated that the endoribonuclease Dicer significantly inhibits the replication of wild-type adenovirus (Ad) via the processing of viral-associated (VA)-RNAs, which are Ad-encoded small noncoding RNAs, and that the knockdown of Dicer leads to enhanced VA-RNA expression and Ad replication after infection with wild-type Ad...
October 19, 2016: Molecular Cancer Therapeutics
Fani-Marlen Roumelioti, Sotirios K Sotiriou, Vasiliki Katsini, Maria Chiourea, Thanos D Halazonetis, Sarantis Gagos
Human malignancies overcome replicative senescence either by activating the reverse-transcriptase telomerase or by utilizing a homologous recombination-based mechanism, referred to as alternative lengthening of telomeres (ALT). In budding yeast, ALT exhibits features of break-induced replication (BIR), a repair pathway for one-ended DNA double-strand breaks (DSBs) that requires the non-essential subunit Pol32 of DNA polymerase delta and leads to conservative DNA replication. Here, we examined whether ALT in human cancers also exhibits features of BIR A telomeric fluorescence in situ hybridization protocol involving three consecutive staining steps revealed the presence of conservatively replicated telomeric DNA in telomerase-negative cancer cells...
October 19, 2016: EMBO Reports
Elsa Vera, Nazario Bosco, Lorenz Studer
Modeling late-onset disorders such as Parkinson's disease (PD) using iPSC technology remains a challenge, as current differentiation protocols yield cells with the properties of fetal-stage cells. Here, we tested whether it is possible to accelerate aging in vitro to trigger late-onset disease phenotypes in an iPSC model of PD. In order to manipulate a factor that is involved in natural aging as well as in premature aging syndromes, we used telomere shortening as an age-inducing tool. We show that shortened telomeres result in age-associated as well as potentially disease-associated phenotypes in human pluripotent stem cell (hPSC)-derived midbrain dopamine (mDA) neurons...
October 18, 2016: Cell Reports
Hanseol Kim, Jihye Ryu, Chaeyoung Lee
A genome-wide association study was conducted to identify expression quantitative trait loci (eQTL) for human telomerase.We tested the genetic associations of nucleotide variants with expression of the genes encoding human telomerase reverse transcriptase (hTERT) and telomerase RNA components (TERC) in lymphoblastoid cell lines derived from 373 Europeans.Our results revealed 6 eQTLs associated with hTERT (P < 5 × 10). One eQTL (rs17755753) was located in the intron 1 of the gene encoding R-spondin-3 (RSPO3), a well-known Wnt signaling regulator...
October 2016: Medicine (Baltimore)
Shigeo Ohba, Joydeep Mukherjee, Tor-Christian Johannessen, Andrew Mancini, Tracy T Chow, Matthew Wood, Lindsey Jones, Tali Mazor, Roxanne E Marshall, Pavithra Viswanath, Kyle M Walsh, Arie Perry, Robert J A Bell, Joanna J Phillips, Joseph F Costello, Sabrina M Ronen, Russell O Pieper
Mutations in the isocitrate dehydrogenase gene IDH1 are common in lower-grade glioma where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation and gliomagenesis. IDH1 mutations also co-segregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine if and how this may occur, we investigated the phenotype of pRb/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H mutant (IDH1mut) genes as they progressed through their lifespan...
October 6, 2016: Cancer Research
Yu Zou, Huei Jinn Tong, Mingming Li, Kai Soo Tan, Tong Cao
The ability of human embryonic stem cells (hESCs) to proliferate indefinitely is attributed to its high telomerase activity and associated long telomere. However, factors regulating telomere length in hESCs remain largely uncharacterized. The aims of this study were, to identify factors which modulate telomere length of hESCs, and to determine if the telomere length of hESCs influences cellular senescence of its differentiated progeny cells. Telomerase reverse transcriptase (TERT) gene expression, telomerase activity and telomere length of hESCs cultured in different culture systems were compared...
October 18, 2016: Biogerontology
Ch Lavanya, M K Sibin, M M Srinivas Bharath, M Jeru Manoj, Manjunatha M Venkataswamy, Dhananjaya I Bhat, K V L Narasinga Rao, G K Chetan
Human telomerase reverse transcriptase (hTERT) gene is a biomarker for the targeted therapy in various cancers. Presence of increased telomerase activity is a common feature of all cancers including glioblastoma. Both RNA and catalytic subunits of hTERT are the target sites for blocking its activity. The current study focuses on the expression of hTERT in glioblastoma and its regulation using two different novel siRNAs (small interfering RNA). Our patient data demonstrated increased expression of hTERT, which could be correlated with carcinogenesis in glioma...
October 18, 2016: Cytotechnology
Karima Ait-Aissa, Joseph Hockenberry, David Gutterman, Aron Geurts, Andreas Beyer
OBJECTIVE: Flow mediated dilation (FMD) is the most physiological relevant form of endothelial-mediated vasodilation. Our laboratory has previously shown that telomerase, a ribo-nucleoprotein that counteracts telomere shortening, has a protective effect on endothelial function under conditions of oxidative stress in the human microcirculation. In the presence of coronary artery disease, decreased telomerase activity contributes to a shift in the mediator of FMD from atheroprotective nitric oxide (NO) to pro-inflammatory and atherogenic hydrogen peroxide (H2O2)...
September 2016: Journal of Hypertension
O Sakiragaoglu, A L Munn
To inhibit telomerase activity, a construct which contains artificial introns in the enhanced green fluorescent protein (EGFP) gene that encodes small hairpin RNA (shRNA) sequences that target human telomerase reverse transcriptase (hTERT) gene expression was designed and tested for its effect on lung cancer cell line. On intron splicing from the construct, intronic sequences were released and formed shRNA in the cells. After transfection of the construct, hTERT mRNA expression decreased by approximately 55 % in A549 cells...
October 17, 2016: Molecular Biotechnology
Wafaa M Ezzat, Khalda Said Amr, Haiam Abdel Raouf, Yasser A Elhosary, Abdelfattah E Hegazy, Hoda H Fahim, Refaat R Kamel
BACKGROUND AND AIMS: Activation of telomerase reverse transcriptase (hTERT) has a role in liver carcinogenesis where telomerase is normally suppressed in most human somatic tissues after birth. In the current study we aimed to detect the significance of hTERT mRNA in early detection of hepatocellular carcinoma (HCC) and to determine the relationship between serum microRNA155 and telomerase expression. METHODS: Serum and liver tissue samples were collected from 40 patients (17 samples from patients with liver cirrhosis and 23 samples from patients with HCC) and 12 blood samples from healthy subjects were collected...
July 2016: Archives of Medical Research
Karla Schmitt, Fabian Beier, Jens Panse, Tim H Brümmendorf
Telomere syndromes (syn. Telomeropathies) are inherited disorders hallmarked by accelerated telomere shortening based on a molecular defect within the telomerase/telomere complex. The rare, but well-defined model disorder Dyskeratosis congenita (DKC) characterized by typical skin manifestations and bone marrow failure represents the classical manifestation of telomere syndromes in childhood and adolescence. However, cryptic variants of DKC, clinically manifest through appearance of atypical bone marrow failure, lung fibrosis or liver cirrhosis - especially in adults up to the fifth decade of age - are frequently underdiagnosed...
October 2016: Deutsche Medizinische Wochenschrift
Fa-Min Zeng, Yang-Min Xie, Lian-Di Liao, Li-Yan Li, Bo Chen, Jian-Jun Xie, Li-Yan Xu, En-Min Li
The key molecular events that contribute to tumorigenesis are incompletely understood. The aim of the present study was to characterize and compare the biological phenotypes of three human telomerase reverse transcriptase (hTERT) and/or human papillomavirus 16 E6 and E7‑immortalized esophageal epithelial cell lines, NE2‑hTERT (NE2), NE3‑E6E7‑hTERT (NE3) and NEcA6‑E6E7‑hTERT (NEcA6). The present study used soft‑agar colony formation assays, tumorigenicity assays in nude mice, and cell proliferation, adhesion and migration assays to identify the biological characteristics of NE2, NE3 and NEcA6 cells...
October 6, 2016: Molecular Medicine Reports
Yanjun Wang, Luzhu Yang, Baoxin Li, Yan Jin
As a universal biomarker, telomerase is one of the promising targets for cancer diagnosis and therapy. Therefore, it is meaningful to develop facile, robust and sensitive methods for evaluation of telomerase activity. Herein, combined with fluorescence resonance energy transfer (FRET), we creatively designed a gold nanorod (GNR)-based FRET method to detect telomerase activity from cell extracts. As the signal probe, carboxyfluorescein-modified DNA probes (F-DNA) hold negative electricity. The electrostatic interaction between F-DNA and positively charged GNRs makes F-DNA close to GNRs, which leads to weak FRET between the F-DNA and GNRs...
October 17, 2016: Analyst
Irina D Strazhesko, Olga N Tkacheva, Dariga U Akasheva, Ekaterina N Dudinskaya, Ekaterina V Plokhova, Valentina S Pykhtina, Anna S Kruglikova, Natalia V Kokshagina, Natalia V Sharashkina, Mikhail V Agaltsov, Daria A Kashtanova, Vladimir A Vygodin, Irina N Ozerova, Dmitry A Skvortsov, Daria Vasilkova, Sergey A Boytsov
Background: Telomerase activity (TA) is considered as the biomarker for cardiovascular aging and cardiovascular diseases (CVDs). Recent studies suggest a link between statins and telomere biology that may be explained by anti-inflammatory actions of statins and their positive effect on TA. Until now, this effect has not been investigated in prospective randomized studies. We hypothesized that 12 months of atorvastatin therapy increased TA in peripheral blood mononuclear cells. Methods: In a randomized, placebo-controlled study 100 hypercholesterolemic patients, aged 35-75 years, free of known CVDs and diabetes mellitus type 2 received 20 mg of atorvastatin daily or placebo for 12 months...
2016: Frontiers in Pharmacology
Diqi Yang, Lei Wang, Pengfei Lin, Tingting Jiang, Nan Wang, Fan Zhao, Huatao Chen, Keqiong Tang, Dong Zhou, Aihua Wang, Yaping Jin
With granulosa and theca cells, the ovaries are responsible for producing oocytes and secreting sex steroids such as estrogen and progesterone. Endoplasmic reticulum stress (ERS) plays an important role in follicle atresia and embryo implantation. In this study, goat granulosa cells were isolated from medium-sized (4-6 mm) healthy follicles. Primary granulosa cells were immortalized by transfection with human telomerase reverse transcriptase (hTERT) to establish a goat granulosa cell line (hTERT-GGCs). These hTERT-GGCs expressed hTERT and had relatively long telomeres at passage 50...
October 15, 2016: Journal of Reproduction and Development
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