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DNA damage

Asmaa E Kassab, Ehab M Gedawy
As we are interested in synthetizing biologically active leads with dual anticancer and antibacterial activity, we adopted biology oriented drug synthesis (BIODS) strategy to synthesize a series of novel ciprofloxacin (CP) hybrids. The National Cancer Institute (USA) selected seventeen newly synthesized compounds for anticancer evaluation against 59 different human tumor cell lines. Five compounds 3e, 3f, 3h, 3o and 3p were further studied through determination of IC50 values against the most sensitive cancer cell lines...
March 9, 2018: European Journal of Medicinal Chemistry
Neha J Pancholi, Matthew D Weitzman
During viral replication in the nucleus, the DNA genomes of adenoviruses are accessible to cellular DNA-binding proteins. Human adenovirus type 5 (Ad5) targets the cellular Mre11-Rad50-Nbs1 complex (MRN) to evade detection by the DNA damage response (DDR). Ad5 mutants that cannot target MRN have reduced viral propagation. Previous studies showed that diverse adenovirus serotypes interact differently with MRN. While these studies revealed diverse MRN interactions among serotypes, it remains unclear how these differences influence viral replication...
March 13, 2018: Virology
Teresa Morales-Ruiz, Álvaro C Romero-Valenzuela, Vanessa M Vázquez-Grande, Teresa Roldán-Arjona, Rafael R Ariza, Dolores Córdoba-Cañero
Base excision repair (BER) is a major defense pathway against spontaneous DNA damage. This multistep process is initiated by DNA glycosylases that recognise and excise the damaged base, and proceeds by the concerted action of additional proteins that perform incision of the abasic site, gap filling and ligation. BER has been extensively studied in bacteria, yeasts and animals. Although knowledge of this pathway in land plants is increasing, there are no reports detecting BER in algae. We describe here an experimental in vitro system allowing the specific analysis of BER in the model alga Chlamydomonas reinhardtii...
March 5, 2018: DNA Repair
Tales Rocha de Moura, Sina Mozaffari-Jovin, Csaba Zoltán Kibédi Szabó, Jana Schmitzová, Olexandr Dybkov, Constantin Cretu, Michael Kachala, Dmitri Svergun, Henning Urlaub, Reinhard Lührmann, Vladimir Pena
Human nineteen complex (NTC) acts as a multimeric E3 ubiquitin ligase in DNA repair and splicing. The transfer of ubiquitin is mediated by Prp19-a homotetrameric component of NTC whose elongated coiled coils serve as an assembly axis for two other proteins called SPF27 and CDC5L. We find that Prp19 is inactive on its own and have elucidated the structural basis of its autoinhibition by crystallography and mutational analysis. Formation of the NTC core by stepwise assembly of SPF27, CDC5L, and PLRG1 onto the Prp19 tetramer enables ubiquitin ligation...
March 15, 2018: Molecular Cell
Radoslav Aleksandrov, Anton Dotchev, Ina Poser, Dragomir Krastev, Georgi Georgiev, Greta Panova, Yordan Babukov, Georgi Danovski, Teodora Dyankova, Lars Hubatsch, Aneliya Ivanova, Aleksandar Atemin, Marina N Nedelcheva-Veleva, Susanne Hasse, Mihail Sarov, Frank Buchholz, Anthony A Hyman, Stephan W Grill, Stoyno S Stoynov
A single mutagen can generate multiple different types of DNA lesions. How different repair pathways cooperate in complex DNA lesions, however, remains largely unclear. Here we measured, clustered, and modeled the kinetics of recruitment and dissociation of 70 DNA repair proteins to laser-induced DNA damage sites in HeLa cells. The precise timescale of protein recruitment reveals that error-prone translesion polymerases are considerably delayed compared to error-free polymerases. We show that this is ensured by the delayed recruitment of RAD18 to double-strand break sites...
March 15, 2018: Molecular Cell
Dong-Keon Lee, Ji-Hee Kim, Joohwan Kim, Seunghwan Choi, MinSik Park, Wonjin Park, Suji Kim, Kyu-Sun Lee, Taesam Kim, Jiwon Jung, Yoon Kyung Choi, Kwon-Soo Ha, Moo-Ho Won, Timothy R Billiar, Young-Guen Kwon, Young-Myeong Kim
Regulated in development and DNA damage responses (REDD)-1, an inhibitor of mammalian target of rapamycin (mTOR), is induced by various cell stressors, including LPS, a major player in the pathogenesis of endotoxemic shock. However, the pathologic role of REDD-1 in endotoxemia is largely unknown. We found that LPS increased REDD-1 expression, nuclear transcription factor-κB (NF-κB) activation, and inflammation and that these responses were suppressed by REDD-1 knockdown and in REDD-1+/- macrophages. REDD-1 overexpression stimulated NF-κB-dependent inflammation without additional LPS stimulation...
March 16, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Richard Garrett Morgan, Anthony J Donato, Ashley E Walker
While most telomere biology research continues to focus on telomere shortening, there is increasing evidence that telomere deprotection, or "uncapping", is more biologically and possibly clinically important. Telomeres form t-loops to prevent the chromosome ends from appearing as a double-stranded DNA break and initiating a DNA damage response. Breakdown of the t-loop structure, referred to as uncapping, can lead to cellular senescence and increased oxidative stress and inflammation in tissues. In this review, we will describe how telomere uncapping potentially leads to age-related vascular dysfunction, and increased cellular senescence, oxidative stress, and inflammation...
March 16, 2018: American Journal of Physiology. Heart and Circulatory Physiology
Yutaka Ikeda, Yukio Nagasaki
Oxidative stress caused by reactive oxygen species (ROS) occurs as events in which living tissues contact certain materials. These events include cell cultures and implantation of materials. Because of the high reactivity of ROS, they damage cells by oxidizing DNA, lipids, and proteins. Conversely, ROS also act as signaling molecules regulating cellular morphology. In particular, mitochondrial ROS are involved in the regulation of cellular physiology, including differentiation, autophagy, metabolic adaptation, apoptosis, and immunity...
March 16, 2018: Biomedical Materials
Meiguang Xiong, Suyun Wang, Yan-Yi Wang, Yong Ran
The cGAS-MITA pathway of cytosolic DNA sensing plays essential roles in immune response against pathogens that contain DNA or with DNA production in their life cycles. The cGAS-MITA pathway also detects leaked or aberrant accumulated self DNA in the cytoplasm under certain pathological conditions, such as virus induced cell death, DNA damage, mitochondria damage, gene mutations, which results in autoimmune diseases. Therefore, the cGAS-MITA pathway must be tightly controlled to ensure proper immune response against pathogens and to avoid autoimmune diseases...
March 15, 2018: Virologica Sinica
Lisa Menegazzo, Valentina Scattolini, Roberta Cappellari, Benedetta Maria Bonora, Mattia Albiero, Mario Bortolozzi, Filippo Romanato, Giulio Ceolotto, Saula Vigili de Kreutzeberg, Angelo Avogaro, Gian Paolo Fadini
AIMS: Diabetes is associated with an excess release of neutrophil extracellular traps (NETs) and an enhanced NETosis, a neutrophil cell death programme instrumental to anti-microbial defences, but also involved in tissue damage. We herein investigated whether the antidiabetic drug metformin protects against NETosis. METHODS: We measured NET components in the plasma of patients with pre-diabetes who were randomized to receive metformin or placebo for 2 months. To control for the effect on glucose, we also measured NET components in the plasma of patients with type 2 diabetes before and after treatment with insulin or dapagliflozin...
March 15, 2018: Acta Diabetologica
Fabien Bernard, Sylvain Dumez, Sébastien Lemière, Anne Platel, Fabrice Nesslany, Annabelle Deram, Franck Vandenbulcke, Damien Cuny
Cadmium (Cd) is a highly toxic element for living organisms and is widespread in metal-contaminated soils. As organisms which can grow up on these polluted areas, plants have some protection mechanisms against Cd issues. Among the plant kingdom, the Brassicaceae family includes species which are known to be able to tolerate and accumulate Cd in their tissues. In this study, Brassica oleracea var. viridis cv "Prover" was exposed to a range of artificially Cd-contaminated soils (from 2.5 up to 20 mg kg-1 ) during 3, 10, and 56 days and the effects on life traits, photosynthesis activity, antioxidant enzymatic activities were studied...
March 15, 2018: Environmental Science and Pollution Research International
Yang Chen, Youyou Wang, Lujun Zhao, Ping Wang, Jifeng Sun, Rudi Bao, Chenghai Li, Ningbo Liu
Objective: To investigate the potential of HS-10182, a second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), as a radiosensitizer in non-small cell lung cancer (NSCLC). Methods: Two cell lines of NSCLCs, A549 that possesses wild-type (WT) EGFRs and H1975 that possesses EGFR L858R/T790M double mutations, were treated with HS-10182 at various concentrations, and cell viabilities were determined using the MTS assay. The cells were tested by clonogenic survival assays to identify the radiosensitivity of both groups...
February 2018: Cancer Biology & Medicine
Francesca Vena, Ruochen Jia, Arman Esfandiari, Juan J Garcia-Gomez, Manuel Rodriguez-Justo, Jianguo Ma, Sakeena Syed, Lindsey Crowley, Brian Elenbaas, Samantha Goodstal, John A Hartley, Daniel Hochhauser
Targeting the DNA damage response (DDR) in tumors with defective DNA repair is a clinically successful strategy. The RAS/RAF/MEK/ERK signalling pathway is frequently deregulated in human cancers. In this study, we explored the effects of MEK inhibition on the homologous recombination pathway and explored the potential for combination therapy of MEK inhibitors with DDR inhibitors and a hypoxia-activated prodrug. We studied effects of combining pimasertib, a selective allosteric inhibitor of MEK1/2, with olaparib, a small molecule inhibitor of poly (adenosine diphosphate [ADP]-ribose) polymerases (PARP), and with the hypoxia-activated prodrug evofosfamide in ovarian and pancreatic cancer cell lines...
February 20, 2018: Oncotarget
Haiyan Qin, Guang Zhang, Lianbo Zhang
Polycomb group genes (PcG) encode chromatin modification proteins that are involved in the epigenetic regulation of cell differentiation, proliferation and the aging processes. The key subunit of the PcG complex, enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), has a central role in a variety of mechanisms, such as the formation of chromatin structure, gene expression regulation and DNA damage. In the present study, ultraviolet A (UVA) was used to radiate human dermal fibroblasts in order to construct a photo-aged cell model...
April 2018: Experimental and Therapeutic Medicine
Sibel Türedi, Esin Yuluğ, Ahmet Alver, Akin Bodur, İmran İnce
The present study evaluated the neuroprotective and antioxidant effects of quercetin in a rat model of sciatic nerve crush injury using histopathological, morphometric and biochemical methods. A total of 48 male Sprague Dawley rats, aged 10-12 weeks old were randomly divided into eight groups, consisting of two sham groups (S-7, S-28), three quercetin-treated groups (Q-7, Q-28; 200 mg/kg/7 days), trauma (T-7, T-28; 1 min sciatic nerve crush injury) and three trauma+quercetin groups (T+Q-7, T+Q-28; trauma+quercetin 200 mg/kg/7 days)...
April 2018: Experimental and Therapeutic Medicine
S Wang, Z Zou, X Luo, Y Mi, H Chang, D Xing
Liver receptor homolog-1 (LRH1) has been shown to promote tumor proliferation and development. However, the functions of LRH1 in mediating cancer cells chemoresistance are still not clear. Here, we found LRH1 levels were significantly elevated in primary breast cancer tissues in patients who developed early recurrence. Similarly, adriamycin (ADR)-resistant breast cancer cell lines also exerted high LRH1 expression. Indeed, overexpression of LRH1 attenuated cytotoxicity of chemotherapeutic drugs ADR and cisplatin (DDP) in breast cancer cells in vitro and in nude mice tumor model...
March 16, 2018: Oncogene
Péter Nagy, Gyöngyvér O Sándor, Gábor Juhász
Intestinal homeostasis is maintained by tightly controlled proliferation and differentiation of tissue-resident multipotent stem cells during aging and regeneration, which ensures organismal adaptation. Here we show that autophagy is required in Drosophila intestinal stem cells to sustain proliferation, and preserves the stem cell pool. Autophagy-deficient stem cells show elevated DNA damage and cell cycle arrest during aging, and are frequently eliminated via JNK-mediated apoptosis. Interestingly, loss of Chk2, a DNA damage-activated kinase that arrests the cell cycle and promotes DNA repair and apoptosis, leads to uncontrolled proliferation of intestinal stem cells regardless of their autophagy status...
March 15, 2018: Scientific Reports
Pingping Fang, Jill A Madden, Lisa Neums, K Ryan Moulder, M Laird Forrest, Jeremy Chien
FOXM1 transcription factor network is activated in over 84% of cases in high-grade serous ovarian cancer (HGSOC), and FOXM1 upregulates the expression of genes involved in the homologous recombination (HR) DNA damage and repair (DDR) pathway. However, the role of FOXM1 in poly (ADP-ribose) polymerase (PARP) inhibitor response has not yet been studied. The present study demonstrates that PARP inhibitor (PARPi), olaparib, induces the expression and nuclear localization of FOXM1. Based on ChIP-qPCR, olaparib enhances the binding of FOXM1 to genes involved in HR repair...
March 15, 2018: Molecular Cancer Research: MCR
Fawaz Awad, Eman Assrawi, Camille Louvrier, Claire Jumeau, Irina Giurgea, Serge Amselem, Sonia-Athina Karabina
Photoaging and epithelial skin tumorigenesis are complex processes triggered mainly by UV radiation from chronic sun exposure. This leads to DNA damage and reactive oxygen species (ROS) production, which initiate an inflammatory response that alters cell structure and function. Changes in cell homeostasis and ROS production activate intracellular multiprotein platforms called inflammasomes. Inflammasomes nucleate around cytoplasmic receptors mainly of the NLR (nucleotide-binding domain and leucine-rich repeat) family and regulate caspase-1-dependant secretion of pro-inflammatory interleukin (IL)-1β and IL-18 cytokines, and an inflammatory form of death named pyroptosis...
March 12, 2018: Mechanisms of Ageing and Development
G Vázquez-Gómez, L Rocha-Zavaleta, M Rodríguez-Sosa, P Petrosyan, J Rubio-Lightbourn
Benzo[a]pyrene (B[a]P), the most extensively studied carcinogen in cigarette smoke, has been regarded as a critical mediator of lung cancer. It is known that B[a]P-mediated Aryl hydrocarbon Receptor (AhR) activation stimulates the mitogen activated protein kinases (MAPK) signaling cascade in different cell models. MAPK pathway disturbances drive alterations in cellular processes, such as differentiation, proliferation, and apoptosis, and the disturbances may also modify the AhR pathway itself. However, MAPK involvement in B[a]P metabolic activation and toxicity in lung tissues is not well understood...
March 12, 2018: Toxicology Letters
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