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https://www.readbyqxmd.com/read/27926505/antitumor-effect-of-combination-of-the-inhibitors-of-two-new-oncotargets-proton-pumps-and-reverse-transcriptase
#1
Luana Lugini, Ilaria Sciamanna, Cristina Federici, Elisabetta Iessi, Enrico Pierluigi Spugnini, Stefano Fais
Tumor therapy needs new approaches in order to improve efficacy and reduce toxicity of the current treatments. The acidic microenvironment and the expression of high levels of endogenous non-telomerase reverse transcriptase (RT) are common features of malignant tumor cells. The anti-acidic proton pump inhibitor Lansoprazole (LAN) and the non-nucleoside RT inhibitor Efavirenz (EFV) have shown independent antitumor efficacy. LAN has shown to counteract drug tumor resistance. We tested the hypothesis that combination of LAN and EFV may improve the overall antitumor effects...
December 3, 2016: Oncotarget
https://www.readbyqxmd.com/read/27925632/sepsis-induces-telomere-shortening-a-potential-mechanism-responsible-for-delayed-pathophysiological-events-in-sepsis-survivors
#2
Naara Mendes Oliveira, Ester C S Rios, Thais Martins de Lima, Vanessa Jacob Victorino, Hermes Barbeiro, Fabiano Pinheiro da Silva, Csaba Szabo, Francisco Garcia Soriano
Sepsis survivors suffer from additional morbidities, including higher disk of readmissions, nervous system disturbances and cognitive dysfunction, and increased mortality, even several years after the initial episode of sepsis. In many ways, the phenotype of sepsis survivors resembles the phenotype associated with accelerated aging. Since telomere shortening is a hallmark of aging, we investigated whether sepsis also leads to telomere shortening. Male balb/c mice were divided into two groups: the control group received 100 μl of normal saline intraperitoneally; the sepsis group received 15 mg/kg of bacterial lipopolysaccharide i...
December 5, 2016: Molecular Medicine
https://www.readbyqxmd.com/read/27922187/tomentosin-induces-telomere-shortening-and-caspase-dependant-apoptosis-in-cervical-cancer-cells
#3
Nawel Merghoub, Hassan El Btaouri, Laila Benbacer, Saïd Gmouh, Chantal Trentesaux, Bertrand Brassart, Mohammed Attaleb, Claudie Madoulet, Thomas Wenner, Saaid Amzazi, Hamid Morjani, Mohamed El Mzibri
Tomentosin, a natural sesquiterpene lactone purified from of Inula viscosa L., was investigated for its anti-proliferative, telomere shortening and apoptotic effects on human cervical cancer HeLa and SiHa cell lines. Tomentosin was found to inhibit the growth of SiHa and HeLa cell lines in dose and time-dependent manner (IC50 values of 7.10 ± 0.78µM and 5.87 ± 0.36µM, respectively after 96h of treatment). As evidenced by TTAGGG telomere length assay, tomentosin target specifically the telomeric overhang lengthening...
December 6, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27918544/a-balance-between-elongation-and-trimming-regulates-telomere-stability-in-stem-cells
#4
Teresa Rivera, Candy Haggblom, Sandro Cosconati, Jan Karlseder
Telomere length maintenance ensures self-renewal of human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs); however, the mechanisms governing telomere length homeostasis in these cell types are unclear. Here, we report that telomere length is determined by the balance between telomere elongation, which is mediated by telomerase, and telomere trimming, which is controlled by XRCC3 and Nbs1, homologous recombination proteins that generate single-stranded C-rich telomeric DNA and double-stranded telomeric circular DNA (T-circles), respectively...
December 5, 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27914369/dna-tetrahedral-scaffolds-based-platform-for-the-construction-of-electrochemiluminescence-biosensor
#5
Qiu-Mei Feng, Zhen Zhou, Mei-Xing Li, Wei Zhao, Jing-Juan Xu, Hong-Yuan Chen
Proximal metallic nanoparticles (NPs) could quench the electrochemiluminescence (ECL) emission of semiconductor quantum dots (QDs) due to Förster energy transfer (FRET), but at a certain distance, the coupling of light-emission with surface plasmon resonance (SPR) result in enhanced ECL. Thus, the modification strategies and distances control between QDs and metallic NPs are critical for the ECL intensity of QDs. In this strategy, a SPR enhanced ECL sensor based on DNA tetrahedral scaffolds modified platform was reported for the detection of telomerase activity...
November 27, 2016: Biosensors & Bioelectronics
https://www.readbyqxmd.com/read/27911794/activation-of-mutant-tert-promoter-by-ras-erk-signaling-is-a-key-step-in-malignant-progression-of-braf-mutant-human-melanomas
#6
Yinghui Li, Hui Shan Cheng, Wee Joo Chng, Vinay Tergaonkar
Although activating BRAF/NRAS mutations are frequently seen in melanomas, they are not sufficient to drive malignant transformation and require additional events. Frequent co-occurrence of mutations in the promoter for telomerase reverse transcriptase (TERT), along with BRAF alterations, has recently been noted and correlated with poorer prognosis, implicating a functional link between BRAF signaling and telomerase reactivation in melanomas. Here, we report that RAS-ERK signaling in BRAF mutant melanomas is critical for regulating active chromatin state and recruitment of RNA polymerase II at mutant TERT promoters...
November 23, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27908660/targeting-of-multiple-senescence-promoting-genes-and-signaling-pathways-by-triptonide-induces-complete-senescence-of-acute-myeloid-leukemia-cells
#7
Yanyan Pan, Mei Meng, Nana Zheng, Zhifei Cao, Ping Yang, Xiaodong Xi, Quansheng Zhou
Leukemia cells aberrantly overexpress senescence-suppression telomerase reverse transcriptase (TERT) and down-regulate key senescence-promoting genes to escape complete senescence, resulting in immortalization and malignant progression. Accordingly, induction of complete senescence is a sensible strategy for anti-leukemia therapy. However, effective senescence-based anti-leukemia drugs with low toxicity are currently lacking. In this study, we found that triptonide (chemical name diterpene triepoxide), a small molecule derived from the herb Tripterygium wilfordii Hook, strongly induced complete senescence in cultured acute myeloid leukemia (AML) cell lines, and potently inhibited growth and colony formation of U937 and HL-60 AML cell line with IC50 values of 7...
November 28, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27904002/diffuse-mesangial-sclerosis-in-a-child-with-dyskeratosis-congenita-leading-to-end-stage-renal-disease
#8
Abidi Kamel, Taha Sayari, Manel Jellouli, Yousra Hammi, Rim Ghoucha Louzir, Tahar Gargah
Dyskeratosis congenita (DC) is a very rare inherited disorder. It is caused by dysfunction of telomere maintenance. It involves RNA telomerase components relevant to various mutations leading to a classic triad of physical findings consisting of nail dystrophy of the hands and feet, mucosal leukoplakia, and reticular pigmentation of the skin, most commonly on the head, neck, and trunk. Bone marrow failure along with pulmonary complications and malignancies are all common causes of premature death in patients with DC as well as other abnormalities...
November 2016: Iranian Journal of Kidney Diseases
https://www.readbyqxmd.com/read/27903905/human-mlh1-suppresses-the-insertion-of-telomeric-sequences-at-intra-chromosomal-sites-in-telomerase-expressing-cells
#9
Pingping Jia, Megan Chastain, Ying Zou, Chengtao Her, Weihang Chai
Aberrant formation of interstitial telomeric sequences (ITSs) promotes genome instabilities. However, it is unclear how aberrant ITS formation is suppressed in human cells. Here, we report that MLH1, a key protein involved in mismatch repair (MMR), suppresses telomeric sequence insertion (TSI) at intra-chromosomal regions. The frequency of TSI can be elevated by double-strand break (DSB) inducer and abolished by ATM/ATR inhibition. Suppression of TSI requires MLH1 recruitment to DSBs, indicating that MLH1's role in DSB response/repair is important for suppressing TSI...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27903649/structural-mechanism-underpinning-cross-reactivity-of-a-cd8-t-cell-clone-that-recognises-a-peptide-derived-from-human-telomerase-reverse-transcriptase
#10
David K Cole, Hugo A van den Berg, Angharad Lloyd, Michael D Crowther, Konrad Beck, Julia Ekeruche-Makinde, John J Miles, Anna M Bulek, Garry Dolton, Andrea J Schauenburg, Aaron Wall, Anna Fuller, Mathew Clement, Bruno Laugel, Pierre J Rizkallah, Linda Wooldridge, Andrew K Sewell
T-cell cross-reactivity is essential for effective immune surveillance, but has also been implicated as a pathway to autoimmunity. Previous studies have demonstrated that T-cell receptors (TCRs) that focus on a minimal motif within the peptide are able to facilitate a high level of T-cell cross-reactivity. However, the structural database shows that most TCRs exhibit less focussed antigen binding involving contact with more peptide residues. To further explore the structural features that allow the clonally expressed TCR to functionally engage with multiple peptide-major histocompatibility complexes (pMHCs), we examined the ILA1 CD8+ T-cell clone that responds to a peptide sequence derived from human telomerase reverse transcriptase (hTERT)...
November 30, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27901163/synthesis-and-biological-evaluation-of-simplified-pironetin-analogues-with-modifications-in-the-side-chain-and-the-lactone-ring
#11
Steven Roldán, Adrià Cardona, Laura Conesa, Juan Murga, Eva Falomir, Miguel Carda, J Alberto Marco
The preparation of several new analogues of the natural dihydropyrone pironetin is described. They differ from the natural product mainly in the nature of the side chain and the lactone ring. Their cytotoxic activity has been measured. In addition, their interaction with tubulin, their ability to inhibit the secretion of the vascular endothelial growth factor (VEGF) and the expression of angiogenesis and telomerase-related genes have been determined. Unexpectedly, and unlike pironetin, the lactones studied in this work do not interact with tubulin...
November 30, 2016: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/27901098/tumor-specific-delivery-of-biologics-by-a-novel-t-cell-line-hozot
#12
Teppei Onishi, Hiroshi Tazawa, Yuuri Hashimoto, Makoto Takeuchi, Takeshi Otani, Shuji Nakamura, Fuminori Sakurai, Hiroyuki Mizuguchi, Hiroyuki Kishimoto, Yuzo Umeda, Yasuhiro Shirakawa, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara
"Cell-in-cell" denotes an invasive phenotype in which one cell actively internalizes in another. The novel human T-cell line HOZOT, established from human umbilical cord blood, was shown to penetrate a variety of human cancer cells but not normal cells. Oncolytic viruses are emerging as biological therapies for human cancers; however, efficient viral delivery is limited by a lack of tumor-specific homing and presence of pre-existing or therapy-induced neutralizing antibodies. Here, we report a new, intriguing approach using HOZOT cells to transmit biologics such as oncolytic viruses into human cancer cells by cell-in-cell invasion...
November 30, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27900472/tissue-specific-expression-of-telomerase-reverse-transcriptase-gene-variants-in-nicotiana-tabacum
#13
Jana Fišerová Jurečková, Eva Sýkorová, Said Hafidh, David Honys, Jiří Fajkus, Miloslava Fojtová
In tobacco, three sequence variants of the TERT gene have been described. We revealed unbalanced levels of TERT variant transcripts in vegetative tobacco tissues and enhanced TERT transcription and telomerase activity in reproductive tissues. Telomerase is a ribonucleoprotein complex responsible for the maintenance of telomeres, structures delimiting ends of linear eukaryotic chromosomes. In the Nicotiana tabacum (tobacco) allotetraploid plant, three sequence variants (paralogs) of the gene coding for the telomerase reverse transcriptase subunit (TERT) have been described, two of them derived from the maternal N...
November 29, 2016: Planta
https://www.readbyqxmd.com/read/27900047/microrna-138-inhibits-proliferation-migration-and-invasion-through-targeting-htert-in-cervical-cancer
#14
Na Zhou, Dan Fei, Shan Zong, Mingyue Zhang, Ying Yue
A growing body of evidence suggests that microRNA-138 (miR-138) functions as a tumor suppressor, and is involved in tumor initiation, development and metastasis in certain types of human cancers. However, the function and underlying molecular mechanism of miR-138 in cervical cancer remains unclear. Therefore, the purpose of the present study was to investigate the clinical significance of miR-138 expression in cervical cancer, and to evaluate its role and underlying mechanisms in cervical cancer. The present study indicated that miR-138 expression was significantly downregulated in cervical cancer tissues and cell lines, and that the low miR-138 expression was negatively associated with advanced FIGO stage and lymph node metastasis (P<0...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27899638/structure-and-folding-of-the-tetrahymena-telomerase-rna-pseudoknot
#15
Darian D Cash, Juli Feigon
Telomerase maintains telomere length at the ends of linear chromosomes using an integral telomerase RNA (TER) and telomerase reverse transcriptase (TERT). An essential part of TER is the template/pseudoknot domain (t/PK) which includes the template, for adding telomeric repeats, template boundary element (TBE), and pseudoknot, enclosed in a circle by stem 1. The Tetrahymena telomerase holoenzyme catalytic core (p65-TER-TERT) was recently modeled in our 9 Å resolution cryo-electron microscopy map by fitting protein and TER domains, including a solution NMR structure of the Tetrahymena pseudoknot...
November 29, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27899264/cyclic-ferrocenylnaphthalene-diimide-derivative-as-a-new-class-of-g-quadruplex-dna-binding-ligand
#16
Md Monirul Islam, Shinobu Sato, Shingo Shinozaki, Shigeori Takenaka
To identify an effective ligand that binds to a G-quadruplex structure but not a double-stranded DNA (dsDNA), a set of biophysical and biochemical experiments were carried out using newly synthesized cyclic ferrocenylnaphthalene diimide (cFNDI, 1) or the non-cyclic derivative (2) with various structures of G-quadruplex DNAs and dsDNA. Compound 1 bound strongly to G-quadruplexes DNAs (10(6)M(-1) order) with diminished binding to dsDNA (10(4)M(-1) order) in 100mM AcOH-AcOK buffer (pH 5.5) containing 100mM KCl...
November 15, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27898217/increased-telomerase-reverse-transcriptase-expression-associates-with-spontaneous-exit-from-m-ii-arrest-in-rat-eggs
#17
Shilpa Prasad, Shail K Chaube
In mammals, postovulatory egg aging deteriorates egg quality possibly by mediating spontaneous exit from metaphase-II (M-II) arrest and/or inducing apoptosis. To test this possibility, present study was designed to investigate telomerase reverse transcriptase (TERT) expression, Bcl2 expression, and DNA fragmentation during postovulatory egg aging in vivo, as well as in vitro. Results suggest that postovulatory egg aging induced a time-dependent increase in the number of eggs undergoing spontaneous exit from M-II arrest in vivo, as well as in vitro...
November 29, 2016: Cellular Reprogramming
https://www.readbyqxmd.com/read/27898051/preparation-of-6-8-11-amino-chloro-oxoisoaporphine-and-group-10-metal-complexes-and-evaluation-of-their-in-vitro-and-in-vivo-antitumor-activity
#18
Qi-Pin Qin, Jiao-Lan Qin, Ting Meng, Gui-Ai Yang, Zu-Zhuang Wei, Yan-Cheng Liu, Hong Liang, Zhen-Feng Chen
A series of group-10 metal complexes 1-14 of oxoisoaporphine derivatives were designed and synthesized. 1-14 were more selectively cytotoxic to Hep-G2 cells comparing with normal liver cells. In vitro cytotoxicity results showed that complexes 1-6, 7, 8, 10 and 11, especially 3, were telomerase inhibitors targeting c-myc, telomeric, and bcl-2 G4s and triggered cell senescence and apoptosis; they also caused telomere/DNA damage and S phase arrest. In addition, 1-6 also caused mitochondrial dysfunction. Notably, 3 with 6-amino substituted ligand L(a) exhibited less side effects than 6 with 8-amino substituted ligand L(b) and cisplatin, but similar tumor growth inhibition efficacy in BEL-7402 xenograft model...
November 29, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27895115/shared-subunits-of-tetrahymena-telomerase-holoenzyme-and-replication-protein-a-have-different-functions-in-different-cellular-complexes
#19
Heather E Upton, Henry Chan, Juli Feigon, Kathleen Collins
In most eukaryotes, telomere maintenance relies on telomeric repeat synthesis by a reverse transcriptase named telomerase. To synthesize telomeric repeats, the catalytic subunit telomerase reverse transcriptase (TERT) uses the RNA subunit (TER) as a template. In the ciliate Tetrahymena thermophila,the telomerase holoenzyme consists of TER, TERT, and eight additional proteins including the telomeric-repeat single-stranded DNA binding protein Teb1 and its heterotrimer partners Teb2 and Teb3. Teb1 is paralogous to the large subunit of the general single-stranded DNA binding heterotrimer Replication Protein A (RPA)...
November 28, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27894394/differences-of-cell-surface-marker-expression-between-bone-marrow-and-kidney-derived-murine-mesenchymal-stromal-cells-and-fibroblasts
#20
F Cakiroglu, J W Osbahr, J Kramer, J Rohwedel
Mesenchymal stromal cells (MSC) are undifferentiated, multipotent adult cells with regenerative properties. They are particularly relevant for therapeutic approaches due to the simplicity of their isolation and cultivation. Since MSC show an expression pattern of cell surface marker, which is almost identical to fibroblasts, many attempts have been made to address the similarities and differences between MSC and fibroblasts. In this study we aimed to isolate murine MSC from bone marrow (BM) and kidney to characterize them in comparison to fibroblasts...
October 31, 2016: Cellular and Molecular Biology
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