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https://www.readbyqxmd.com/read/28726787/alkbh7-drives-a-tissue-and-sex-specific-necrotic-cell-death-response-following-alkylation-induced-damage
#1
Jennifer J Jordan, Sophea Chhim, Carrie M Margulies, Mariacarmela Allocca, Roderick T Bronson, Arne Klungland, Leona D Samson, Dragony Fu
Regulated necrosis has emerged as a major cell death mechanism in response to different forms of physiological and pharmacological stress. The AlkB homolog 7 (ALKBH7) protein is required for regulated cellular necrosis in response to chemotherapeutic alkylating agents but its role within a whole organism is unknown. Here, we show that ALKBH7 modulates alkylation-induced cellular death through a tissue and sex-specific mechanism. At the whole-animal level, we find that ALKBH7 deficiency confers increased resistance to MMS-induced toxicity in male but not female mice...
July 20, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28718810/dna2-an-important-player-in-dna-damage-response-or-just-another-dna-maintenance-protein
#2
REVIEW
Elzbieta Pawłowska, Joanna Szczepanska, Janusz Blasiak
The human DNA2 (DNA replication helicase/nuclease 2) protein is expressed in both the nucleus and mitochondria, where it displays ATPase-dependent nuclease and helicase activities. DNA2 plays an important role in the removing of long flaps in DNA replication and long-patch base excision repair (LP-BER), interacting with the replication protein A (RPA) and the flap endonuclease 1 (FEN1). DNA2 can promote the restart of arrested replication fork along with Werner syndrome ATP-dependent helicase (WRN) and Bloom syndrome protein (BLM)...
July 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28714034/inhibition-of-nampt-decreases-cell-growth-and-enhances-susceptibility-to-oxidative-stress
#3
Renhua Xu, Zhenwei Yuan, Lijuan Yang, Lele Li, Dan Li, Changjun Lv
Nicotinamide adenine dinucleotide (NAD) is an essential molecule for living organisms and plays a vital role in aging and age-associated diseases. In eukaryotic cells, cellular NAD is mainly generated by the scavenge pathway in which nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the formation of nicotinamide mononucleotide. Inhibition of NAMPT is a therapeutic strategy for cancer treatment. To explore the effects of NAMPT inhibition on cellular processes, cells were treated with 10 nM FK866, an NAMPT inhibitor, resulting in a decrease in the cellular NAD level, a lower growth rate, and enhanced susceptivity to oxidative stress as compared to the untreated cells...
July 6, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28713907/roles-of-mir%C3%A2-4463-in-h2o2%C3%A2-induced-oxidative-stress-in-human-umbilical-vein-endothelial-cells
#4
Xueqin Wang, Xuemei He, Xian Deng, Yanzheng He, Xiangyu Zhou
Oxidative stress is implicated in the pathophysiology of vascular diseases, including atherosclerosis, aneurysm and arteriovenous fistula. A previous study from our lab suggested that microRNA (miR)‑4463 may be involved in the pathogenesis of vascular disease; however, the roles of oxidative stress in the molecular mechanisms underlying the actions of miR‑4463 in vascular disease have yet to be elucidated. The aim of the present study was to investigate the role of miR‑4463 in hydrogen peroxide (H2O2)‑induced oxidative stress in human umbilical vein endothelial cells (HUVECs)...
July 15, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28710029/decreased-expression-level-of-ber-genes-in-alzheimer-s-disease-patients-is-not-derivative-of-their-dna-methylation-status
#5
Agnieszka Sliwinska, Przemysław Sitarek, Monika Toma, Piotr Czarny, Ewelina Synowiec, Renata Krupa, Paulina Wigner, Katarzyna Bialek, Dominik Kwiatkowski, Anna Korycinska, Ireneusz Majsterek, Janusz Szemraj, Piotr Galecki, Tomasz Sliwinski
BACKGROUND: Neurodegeneration in Alzheimer's disease can be caused by accumulation of oxidative DNA damage resulting from altered expression of genes involved in the base excision repair system (BER). Promoter methylation can affect the profile of BER genes expression. Decreased expression of BER genes was observed in the brains of AD patients. AIM OF THE STUDY: The aim of our study was to compare the expression and methylation profiles of six genes coding for proteins involved in BER, namely: hOGG1, APE1, MUTYH, NEIL1, PARP1 and XRCC1, in the peripheral blood cells of AD patients and healthy volunteers...
July 11, 2017: Progress in Neuro-psychopharmacology & Biological Psychiatry
https://www.readbyqxmd.com/read/28698968/inhibition-of-poly-adp-ribose-polymerase-1-enhances-gene-expression-of-selected-sirtuins-and-app-cleaving-enzymes-in-amyloid-beta-cytotoxicity
#6
Przemysław L Wencel, Walter J Lukiw, Joanna B Strosznajder, Robert Piotr Strosznajder
Poly(ADP-ribose) polymerases (PARPs) and sirtuins (SIRTs) are involved in the regulation of cell metabolism, transcription, and DNA repair. Alterations of these enzymes may play a crucial role in Alzheimer's disease (AD). Our previous results indicated that amyloid beta (Aβ) peptides and inflammation led to activation of PARP1 and cell death. This study focused on a role of PARP1 in the regulation of gene expression for SIRTs and beta-amyloid precursor protein (βAPP) cleaving enzymes under Aβ42 oligomers (AβO) toxicity in pheochromocytoma cells (PC12) in culture...
July 12, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28698806/epigallocatechin-3-gallate-enhances-er-stress-induced-cancer-cell-apoptosis-by-directly-targeting-parp16-activity
#7
Juanjuan Wang, Chenggang Zhu, Dan Song, Ruiqi Xia, Wenbo Yu, Yongjun Dang, Yiyan Fei, Long Yu, Jiaxue Wu
Poly(ADP-ribose) polymerases (PARPs) are ADP-ribosylating enzymes and play important roles in a variety of cellular processes. Most small-molecule PARP inhibitors developed to date have been against PARP1, a poly-ADP-ribose transferase, and suffer from poor selectivity. PARP16, a mono-ADP-ribose transferase, has recently emerged as a potential therapeutic target, but its inhibitor development has trailed behind. Here we newly characterized epigallocatechin-3-gallate (EGCG) as a potential inhibitor of PARP16...
2017: Cell Death Discovery
https://www.readbyqxmd.com/read/28695513/methodology-to-identify-poly-adp-ribose-polymerase-1-parp1-mrna-targets-by-par-clip
#8
Manana Mekishvili, Elena Matveeva, Yvonne Fondufe-Mittendorf
There is a long list of important RNA-binding proteins (RBP) involved in different steps of gene expression through posttranscriptional modifications: pre-mRNA splicing, mRNA stabilization, polyadenylation, mRNA export from nucleus to the cytoplasm, and translation. The critical role of RNA-protein interaction necessitates a continuous identification of proteins involved in this process. Here we describe the identification of Poly-ADP-Ribose Polymerase 1 (PARP1) as an RNA binding protein involved in RNA splicing...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28695512/approaches-for-investigating-translational-regulation-controlled-by-parp1-biotin-based-uv-cross-linking-and-luciferase-reporter-assay
#9
Yingbiao Ji
The RNA-binding proteins (RBPs) play a pivotal role in controlling gene expression through posttranscriptional processes. As the trans-acting factors, RBPs interact with the cis-regulatory elements located within mRNAs to regulate mRNA translational efficiency. Adding a new-layer regulation, recent studies suggest that poly(ADP-ribosyl)ation of the RNA-binding proteins often inhibit the RNA-binding ability of RBPs, thus regulating RBP-dependent mRNA metabolism including translational control. Here, we describe a biotin-based UV cross-linking method to determine if excessive accumulation of pADPr in the cell disrupts the interaction between RBPs and their target mRNAs...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28695510/poly-adp-ribose-dependent-chromatin-remodeling-in-dna-repair
#10
Théo Lebeaupin, Rebecca Smith, Sébastien Huet, Gyula Timinszky
The tightly packed and dynamic structure of chromatin can undergo major reorganization in response to endogenous or exogenous stimuli, such as the regulation of transcription or the cell cycle, or following DNA damage. A fast and local chromatin decondensation is observed upon DNA damage induced by laser micro-irradiation. This decondensation is under the control of poly(ADP-ribosyl)ation (PARylation) by PARP1, one of the first proteins recruited at the DNA damage sites. This chapter provides a step-by-step guide to perform and analyze chromatin decondensation upon DNA damage induction...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28695502/compartment-specific-poly-adp-ribose-formation-as-a-biosensor-for-subcellular-nad-pools
#11
Magali R VanLinden, Marc Niere, Andrey A Nikiforov, Mathias Ziegler, Christian Dölle
Nicotinamide adenine dinucleotide (NAD) is vital to many cellular processes and is distributed between distinct subcellular pools in the compartmentalized eukaryotic cell. The detection and relative quantification of these individual pools is difficult because of the methods usually applied, which require cell disruption and fractionation.Here, we describe an immunochemical method to visualize and relatively quantify subcellular NAD(+) pools, which relies on the NAD(+)-consuming activity of poly-ADP-ribose polymerase 1 (PARP1)...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28692916/discovery-mechanism-and-metabolism-studies-of-2-3-difluorophenyl-linker-containing-parp1-inhibitors-with-enhanced-in%C3%A2-vivo-efficacy-for-cancer-therapy
#12
Wenhua Chen, Ne Guo, Minghui Qi, Haiying Dai, Minghuang Hong, Longfei Guan, Xiajuan Huan, Shanshan Song, Jinxue He, Yingqing Wang, Yong Xi, Xinying Yang, Yanyan Shen, Yi Su, Yiming Sun, Yinglei Gao, Yi Chen, Jian Ding, Yun Tang, Guobin Ren, Zehong Miao, Jian Li
Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially breast and ovarian cancers, and tumor cell lines deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, with the help of molecular docking, we identified a novel series of 2,3-difluorophenyl-linker analogues (15-54) derived from olaparib (1) as PARP1 inhibitors. Lead optimization led to the identification of 47, which showed high selectivity and high potency against PARP1 enzyme (IC50 = 1...
June 27, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28687790/chronic-inflammation-triggered-by-the-nlrp3-inflammasome-in-myeloid-cells-promotes-growth-plate-dysplasia-by-mesenchymal-cells
#13
Chun Wang, Can-Xin Xu, Yael Alippe, Chao Qu, Jianqiu Xiao, Ernestina Schipani, Roberto Civitelli, Yousef Abu-Amer, Gabriel Mbalaviele
Skeletal complications are common features of neonatal-onset multisystem inflammatory disease (NOMID), a disorder caused by NLRP3-activating mutations. NOMID mice in which NLRP3 is activated globally exhibit several characteristics of the human disease, including systemic inflammation and cartilage dysplasia, but the mechanisms of skeletal manifestations remain unknown. In this study, we find that activation of NLRP3 in myeloid cells, but not mesenchymal cells triggers chronic inflammation, which ultimately, causes growth plate and epiphyseal dysplasia in mice...
July 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28687616/post-transcriptional-regulation-of-parg-mrna-by-hur-facilitates-dna-repair-and-resistance-to-parp-inhibitors
#14
Saswati N Chand, Mahsa Zarei, Matthew J Schiewer, Akshay R Kamath, Carmella Romeo, Shruti Lal, Joseph A Cozzitorto, Avinoam Nevler, Laura Scolaro, Eric Londin, Wei Jiang, Nicole Meisner-Kober, Michael J Pishvaian, Karen E Knudsen, Charles J Yeo, John M Pascal, Jordan M Winter, Jonathan R Brody
The majority of pancreatic ductal adenocarcinomas (PDA) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here we show that CRISPR-Cas9-mediated silencing of the HuR locus increases the relative sensitivity of PDA cells to PARP inhibitors (PARPi). PDA cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, polyADP-ribose glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 3' untranslated region (UTR)...
July 7, 2017: Cancer Research
https://www.readbyqxmd.com/read/28678836/epistasis-in-genomic-and-survival-data-of-cancer-patients
#15
Dariusz Matlak, Ewa Szczurek
Cancer aggressiveness and its effect on patient survival depends on mutations in the tumor genome. Epistatic interactions between the mutated genes may guide the choice of anticancer therapy and set predictive factors of its success. Inhibitors targeting synthetic lethal partners of genes mutated in tumors are already utilized for efficient and specific treatment in the clinic. The space of possible epistatic interactions, however, is overwhelming, and computational methods are needed to limit the experimental effort of validating the interactions for therapy and characterizing their biomarkers...
July 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28676700/the-multifaceted-roles-of-parp1-in-dna-repair-and-chromatin-remodelling
#16
REVIEW
Arnab Ray Chaudhuri, André Nussenzweig
Cells are exposed to various endogenous and exogenous insults that induce DNA damage, which, if unrepaired, impairs genome integrity and leads to the development of various diseases, including cancer. Recent evidence has implicated poly(ADP-ribose) polymerase 1 (PARP1) in various DNA repair pathways and in the maintenance of genomic stability. The inhibition of PARP1 is therefore being exploited clinically for the treatment of various cancers, which include DNA repair-deficient ovarian, breast and prostate cancers...
July 5, 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28670489/heat-shock-protein-70-2-hsp70-2-a-novel-cancer-testis-antigen-that-promotes-growth-of-ovarian-cancer
#17
Namita Gupta, Nirmala Jagadish, Avadhesha Surolia, Anil Suri
Heat shock protein 70-2 (HSP70-2) is known to be involved in tumor progression. However, its molecular role and mechanism in epithelial ovarian cancer (EOC) remains unknown. In the present investigation, we examined the role of HSP70-2 in cell cycle, apoptosis and epithelial mesenchymal transition pathways in EOC cells in in vitro and in-vivo xenograft mouse model. To investigate the role of HSP70-2 in ovarian cancer, plasmid driven short hairpin RNA approach was used to examine HSP70-2 gene and protein expression in ovarian cancer cell line A-10 (origin: serous papillary cystadenocarcinoma), Caov-3 (origin: adenocarcinoma) and SKOV3 (origin: adenocarcinoma; derived from metastatic site: ascites) by RT-PCR, quantitative-PCR, immunohistochemistry and Western blotting...
2017: American Journal of Cancer Research
https://www.readbyqxmd.com/read/28660502/down-regulation-of-parp1-by-mir-891b-sensitizes-human-breast-cancer-cells-to-alkylating-chemotherapeutic-drugs
#18
Shujian Xu, Cui Zhao, Zhongming Jia, Xilong Wang, Yong Han, Zhenlin Yang
PURPOSE: Breast cancer is the most common invasive type of cancer among women. Role of different microRNAs (miRNAs) and poly(ADP-ribose) polymerases (PARPs) in breast cancer has been well established. This study aimed to explore the effects of miR-891b on sensitizing breast cancer cells to alkylating chemotherapeutic drugs through PARPs. METHODS: The expression of miR-891b and PARP1 in human breast cancer cells HCC1806 was overexpressed by transfection with their mimics or expressing vector...
June 28, 2017: Archives of Gynecology and Obstetrics
https://www.readbyqxmd.com/read/28660007/micrornas-modulate-oxidative-stress-in-hypertension-through-parp-1-regulation
#19
Douglas F Dluzen, Yoonseo Kim, Paul Bastian, Yongqing Zhang, Elin Lehrmann, Kevin G Becker, Nicole Noren Hooten, Michele K Evans
Oxidative stress is thought to contribute to aging and age-related diseases, such as cardiovascular and neurodegenerative diseases, and is a risk factor for systemic arterial hypertension. Previously, we reported differential mRNA and microRNA (miRNA) expression between African American (AA) and white women with hypertension. Here, we found that the poly-(ADP-ribose) polymerase 1 (PARP-1), a DNA damage sensor protein involved in DNA repair and other cellular processes, is upregulated in AA women with hypertension...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28655785/a-small-molecule-inhibitor-of-wee1-azd1775-synergizes-with-olaparib-by-impairing-homologous-recombination-and-enhancing-dna-damage-and-apoptosis-in-acute-leukemia
#20
Tamara B Garcia, Jonathan C Snedeker, Dmitry Baturin, Lori Gardner, Susan P Fosmire, Chengjing Zhou, Craig T Jordan, Sujatha Venkataraman, Rajeev Vibhakar, Christopher C Porter
Although some patients with acute leukemia have good prognoses, the prognosis of adult and pediatric patients who relapse or cannot tolerate standard chemotherapy is poor. Inhibition of WEE1 with AZD1775 has been shown to sensitize cancer cells to genotoxic chemotherapies including cytarabine in AML and T-ALL. Inhibition of WEE1 impairs homologous recombination by indirectly inhibiting BRCA2. Thus, we sought to determine if AZD1775 could sensitize cells to the PARP1/2 inhibitor olaparib. We found that combined treatment with AZD1775 and olaparib was synergistic in AML and ALL cells, and this combination impaired proliferative capacity upon drug withdrawal...
June 27, 2017: Molecular Cancer Therapeutics
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