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https://www.readbyqxmd.com/read/28339614/integrin-linked-kinase-regulates-syncytialization-of-bewo-trophoblast-cells%C3%A2
#1
Trina M Butler, Justin A Pater, Daniel J MacPhee
During placental development, mononuclear villous cytotrophoblast cells differentiate and fuse with the overlying syncytiotrophoblast. This process requires the dissolution of E-cadherin (CDH1)-containing adherens junctions in cytotrophoblast. Integrin linked kinase (ILK) can downregulate CDH1 through poly (ADP-ribose) polymerase 1 (PARP1) and Snail-1 (SNAI1) during epithelial-mesenchymal transition. ILK is known to be expressed in cytotrophoblast; thus, the role of a potential ILK-PARP1-SNAI1 pathway in aiding trophoblast syncytialization via the downregulation of CDH1 was examined...
January 27, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28336775/nelf-e-is-recruited-to-dna-double-strand-break-sites-to-promote-transcriptional-repression-and-repair
#2
Samah W Awwad, Enas R Abu-Zhayia, Noga Guttmann-Raviv, Nabieh Ayoub
Double-strand breaks (DSBs) trigger rapid and transient transcription pause to prevent collisions between repair and transcription machineries at damage sites. Little is known about the mechanisms that ensure transcriptional block after DNA damage. Here, we reveal a novel role of the negative elongation factor NELF in blocking transcription activity nearby DSBs. We show that NELF-E and NELF-A are rapidly recruited to DSB sites. Furthermore, NELF-E recruitment and its repressive activity are both required for switching off transcription at DSBs...
March 23, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28336669/a-conserved-nad-binding-pocket-that-regulates-protein-protein-interactions-during-aging
#3
Jun Li, Michael S Bonkowski, Sébastien Moniot, Dapeng Zhang, Basil P Hubbard, Alvin J Y Ling, Luis A Rajman, Bo Qin, Zhenkun Lou, Vera Gorbunova, L Aravind, Clemens Steegborn, David A Sinclair
DNA repair is essential for life, yet its efficiency declines with age for reasons that are unclear. Numerous proteins possess Nudix homology domains (NHDs) that have no known function. We show that NHDs are NAD(+) (oxidized form of nicotinamide adenine dinucleotide) binding domains that regulate protein-protein interactions. The binding of NAD(+) to the NHD domain of DBC1 (deleted in breast cancer 1) prevents it from inhibiting PARP1 [poly(adenosine diphosphate-ribose) polymerase], a critical DNA repair protein...
March 24, 2017: Science
https://www.readbyqxmd.com/read/28316110/proteasome-ubiquitin-receptor-psmd4-is-an-amplification-target-in-breast-cancer-and-may-predict-sensitivity-to-parpi
#4
Marlena S Fejzo, Lee Anderson, Hsiao-Wang Chen, Enrique Guandique, Ondrej Kalous, Dylan Conklin, Dennis J Slamon
Poly(ADP-ribose) polymerase 1 (PARP1) is an enzyme involved in DNA repair under investigation as a chemotherapeutic target. Current randomized phase 3 trials of PARPi in metastatic breast cancer are limited to patients with documented BRCA1/2 mutations and no biomarker of PARPi beyond BRCA status is available. In an effort to identify novel biomarkers for PARP inihibition, we created a cell line (HCC1187/TALRES) resistant to the PARP1 inhibitor talazoparib. Herein we show by array-CGH that HCC1187/TALRES has a selective loss of the proteasome ubiquitin receptor PSMD4 amplicon resulting in significant down-regulation of PSMD4...
March 18, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28302504/mitochondrial-nudix-hydrolases-a-metabolic-link-between-nad-catabolism-gtp-and-mitochondrial-dynamics
#5
Aaron Long, Nina Klimova, Tibor Kristian
NAD(+) catabolism and mitochondrial dynamics are important parts of normal mitochondrial function and are both reported to be disrupted in aging, neurodegenerative diseases, and acute brain injury. While both processes have been extensively studied there has been little reported on how the mechanisms of these two processes are linked. This review focuses on how downstream NAD(+) catabolism via NUDIX hydrolases affects mitochondrial dynamics under pathologic conditions. Additionally, several potential targets in mitochondrial dysfunction and fragmentation are discussed, including the roles of mitochondrial poly(ADP-ribose) polymerase 1(mtPARP1), AMPK, AMP, and intra-mitochondrial GTP metabolism...
March 14, 2017: Neurochemistry International
https://www.readbyqxmd.com/read/28281524/mir-216b-increases-cisplatin-sensitivity-in-ovarian-cancer-cells-by-targeting-parp1
#6
Y Liu, Z Niu, X Lin, Y Tian
Cisplatin resistance hinders the efficacy of chemotherapy in ovarian cancer. MicroRNAs (miRs) have been implicated in drug resistance in anti-cancer chemotherapy. We compared the expression profiles of miRs between cisplatin-resistant and cisplatin-sensitive ovarian cancer cells, and found that miR-216b was significantly downregulated in cisplatin-resistant ovarian cancer cells. To investigate its molecular mechanism, we performed cell viability and apoptosis assays in cisplatin-resistant ovarian cells, and found that miR-216b reduced cell viability and promoted apoptosis...
March 10, 2017: Cancer Gene Therapy
https://www.readbyqxmd.com/read/28272405/parp1-promotes-gene-expression-at-the-post-transcriptiona-level-by-modulating-the-rna-binding-protein-hur
#7
Yueshuang Ke, Yanlong Han, Xiaolan Guo, Jitao Wen, Ke Wang, Xue Jiang, Xue Tian, Xueqing Ba, Istvan Boldogh, Xianlu Zeng
Poly(ADP-ribosyl)ation (PARylation) is mainly catalysed by poly-ADP-ribose polymerase 1 (PARP1), whose role in gene transcription modulation has been well established. Here we show that, in response to LPS exposure, PARP1 interacts with the adenylateuridylate-rich element-binding protein embryonic lethal abnormal vision-like 1 (Elavl1)/human antigen R (HuR), resulting in its PARylation, primarily at site D226. PARP inhibition and the D226 mutation impair HuR's PARylation, nucleocytoplasmic shuttling and mRNA binding...
March 8, 2017: Nature Communications
https://www.readbyqxmd.com/read/28259974/3-hydroxyterphenyllin-a-natural-fungal-metabolite-induces-apoptosis-and-s-phase-arrest-in-human-ovarian-carcinoma-cells
#8
Yaomin Wang, Casey Compton, Gary O Rankin, Stephen J Cutler, Yon Rojanasakul, Youying Tu, Yi Charlie Chen
In the present study, we evaluated 3-Hydroxyter-phenyllin (3-HT) as a potential anticancer agent using the human ovarian cancer cells A2780/CP70 and OVCAR-3, and normal human epithelial ovarian cells IOSE-364 as an in vitro model. 3-HT suppressed proliferation and caused cytotoxicity against A2780/CP70 and OVCAR-3 cells, while it exhibited lower cytotoxicity in IOSE-364 cells. Subsequently, we found that 3-HT induced S phase arrest and apoptosis in a dose-independent manner. Further investigation revealed that S phase arrest was related with DNA damage which mediated the ATM/p53/Chk2 pathway...
March 2, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28257805/jnk1-and-jnk3-play-a-significant-role-in-both-neuronal-apoptosis-and-necrosis-evaluation-based-on-in-vitro-approach-using-tert-butylhydroperoxide-induced-oxidative-stress-in-neuro-2a-cells-and-perturbation-through-3-aminobenzamide
#9
Vijaya Prakash Krishnan Muthaiah, Felicia Mary Michael, Tamilselvi Palaniappan, Sridhar Skylab Rajan, Kirubhanand Chandrasekar, Sankar Venkatachalam
In spinal cord injury (SCI), oxidative stress in the penumbra of the injury site is a characteristic feature. The predominance of necrosis over apoptosis in the ensuing delayed cell death results in progressive waves of necrosis affecting neighboring cells and thus exaggerates the severity of the lesion. Necrosis has been classified into subtypes based on the active molecular players and parthanatos is one among them, which is characterized by the over activation of PARP1 as the pre-mitochondrial event that triggers necrosis...
February 28, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28257697/serious-surprises-for-adp-ribosylation-specificity-hpf1-switches-parp1-specificity-to-ser-residues
#10
Anthony K L Leung
In this issue of Molecular Cell, Bonfiglio et al. (2017) demonstrate that histone PARylation factor 1 (HPF1) is required for PARP1 to attach ADP-ribose groups onto the hydroxyl oxygen of the Ser residues of target substrates, including both PARP1 itself and histones. Here, mechanisms and implications of this unexpected, O-linked ADP-ribosylation are speculated on.
March 2, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28257413/uncovering-precision-phenotype-biomarker-associations-in-traumatic-brain-injury-using-topological-data-analysis
#11
Jessica L Nielson, Shelly R Cooper, John K Yue, Marco D Sorani, Tomoo Inoue, Esther L Yuh, Pratik Mukherjee, Tanya C Petrossian, Jesse Paquette, Pek Y Lum, Gunnar E Carlsson, Mary J Vassar, Hester F Lingsma, Wayne A Gordon, Alex B Valadka, David O Okonkwo, Geoffrey T Manley, Adam R Ferguson
BACKGROUND: Traumatic brain injury (TBI) is a complex disorder that is traditionally stratified based on clinical signs and symptoms. Recent imaging and molecular biomarker innovations provide unprecedented opportunities for improved TBI precision medicine, incorporating patho-anatomical and molecular mechanisms. Complete integration of these diverse data for TBI diagnosis and patient stratification remains an unmet challenge. METHODS AND FINDINGS: The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot multicenter study enrolled 586 acute TBI patients and collected diverse common data elements (TBI-CDEs) across the study population, including imaging, genetics, and clinical outcomes...
2017: PloS One
https://www.readbyqxmd.com/read/28256105/cis-nerolidol-induces-endoplasmic-reticulum-stress-and-cell-death-in-human-hepatocellular-carcinoma-cells-through-extensive-cyp2c19-and-cyp1a2-oxidation
#12
Bruna Isabela Biazi, Thalita Alves Zanetti, Adrivanio Baranoski, Amanda Cristina Corveloni, Mário Sérgio Mantovani
Of late, many studies are attempting to find new molecules with anti-cancer properties, especially those with the capability to inhibit cell growth. The aim of this work was to evaluate nerolidol, a plant-based compound, as its cytotoxicity, genotoxicity, antiproliferative and apoptotic induction, cell cycle, mitochondrial membrane potential, and RT-qPCR of transcripts related to those pathways in the human hepatocellular carcinoma cell line (HepG2/C3A). Only cis-nerolidol (C-NER) demonstrated cytotoxicity (100 to 250 μM) activity and was selected to conduct the following experiments...
March 2, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28254786/clinical-impact-of-tumor-dna-repair-expression-and-t-cell-infiltration-in-breast-cancers
#13
Andrew R Green, Mohammed A Aleskandarany, Reem Ali, Eleanor Grace Hodgson, Suha Atabani, Karen De Souza, Emad Rakha, Ian O Ellis, Srinivasan Madhusudan
Impaired DNA repair drives mutagenicity, which increases neoantigen load and immunogenicity. We investigated the expression of proteins involved in the DNA damage response (ATM, Chk2), double-strand break repair (BRCA1, BLM, WRN, RECQL4, RECQL5, TOPO2A, DNA-PKcs, Ku70/Ku80), nucleotide excision repair (ERCC1), base excision repair (XRCC1, pol β, FEN1, PARP1), and immune responses (CD8, PD-1, PD-L1, FOXP3) in 1269 breast cancers and validated our findings in an independent estrogen receptor (ER)- cohort (n = 279)...
March 2, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28254167/design-synthesis-and-in-vitro-cytotoxicity-studies-of-novel-%C3%AE-carbolinium-bromides
#14
P O Venkataramana Reddy, Shriprada Mishra, Mukund P Tantak, Kumar Nikhil, Rachna Sadana, Kavita Shah, Dalip Kumar
A series of novel β-carbolinium bromides has been synthesized from easily accessible β-carbolines and 1-aryl-2-bromoethanones. The newly synthesized compounds were evaluated for their in vitro anticancer activity. Among the synthesized derivatives, compounds 16l, 16o and 16s exhibited potent anticancer activity with IC50 values of <10μM against tested cancer cell lines. The most potent analogue 16l was broadly active against all the tested cancer cell lines (IC50=3.16-7.93μM). In order to test the mechanism of cell death, we exposed castration resistant prostate cancer cell line (C4-2) to compounds 16l and 16s, which resulted in increased levels of cleaved PARP1 and AO/EB staining, indicating that β-carbolinium salts induce apoptosis in these cells...
February 9, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28251828/enriched-environment-increases-pcna-and-parp1-levels-in-octopus-vulgaris-central-nervous-system-first-evidence-of-adult-neurogenesis-in-lophotrochozoa
#15
Carla Bertapelle, Gianluca Polese, Anna Di Cosmo
Organisms showing a complex and centralized nervous system, such as teleosts, amphibians, reptiles, birds and mammals, and among invertebrates, crustaceans and insects, can adjust their behavior according to the environmental challenges. Proliferation, differentiation, migration, and axonal and dendritic development of newborn neurons take place in brain areas where structural plasticity, involved in learning, memory, and sensory stimuli integration, occurs. Octopus vulgaris has a complex and centralized nervous system, located between the eyes, with a hierarchical organization...
March 2, 2017: Journal of Experimental Zoology. Part B, Molecular and Developmental Evolution
https://www.readbyqxmd.com/read/28249904/nr1d1-recruitment-to-sites-of-dna-damage-inhibits-repair-and-is-associated-with-chemosensitivity-of-breast-cancer
#16
Na-Lee Ka, Tae-Young Na, Hyelin Na, Min-Ho Lee, Han-Su Park, Sewon Hwang, Il-Yong Kim, Je Kyung Seong, Mi-Ock Lee
DNA repair capacity is critical for survival of cancer cells upon therapeutic DNA damage and thus is an important determinant of susceptibility to chemotherapy in cancer patients. In this study, we identified a novel function of nuclear receptor NR1D1 in DNA repair, which enhanced chemosensitivity in breast cancer cells. NR1D1 inhibited both non-homologous end joining and homologous recombination double strand breaks (DSB) repair, and delayed the clearance of γH2AX DNA repair foci that formed after treatment of doxorubicin...
March 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28247536/melatonin-regulates-parp1-to-control-the-senescence-associated-secretory-phenotype-sasp-in-human-fetal-lung-fibroblast-cells
#17
Songtao Yu, Xiaojiao Wang, Peiliang Geng, Xudong Tang, Lisha Xiang, Xin Lu, Jianjun Li, Zhihua Ruan, Jianfang Chen, Ganfeng Xie, Zhe Wang, Juanjuan Ou, Yuan Peng, Xi Luo, Xuan Zhang, Yan Dong, Hongshan Chen, Houjie Liang
Cellular senescence is an important tumor-suppressive mechanism. However, acquisition of a senescence-associated secretory phenotype (SASP) in senescent cells has deleterious effects on the tissue microenvironment and, paradoxically, promotes tumor progression. In a drug screen, we identified melatonin as a novel SASP suppressor in human cells. Strikingly, melatonin blunts global SASP gene expression upon oncogene-induced senescence (OIS). Moreover, poly(ADP-ribose) polymerase-1 (PARP-1), a sensor of DNA damage, was identified as a new melatonin-dependent regulator of SASP gene induction upon OIS...
March 1, 2017: Journal of Pineal Research
https://www.readbyqxmd.com/read/28242752/phase-i-dose-escalation-2-part-trial-of-poly-adp-ribose-polymerase-inhibitor-talazoparib-in-patients-with-advanced-germline-brca1-2-mutations-and-selected-sporadic-cancers
#18
Johann de Bono, Ramesh K Ramanathan, Lida Mina, Rashmi Chugh, John Glaspy, Saeed Rafii, Stan Kaye, Jasgit Sachdev, John Heymach, David C Smith, Joshua W Henshaw, Ashleigh Herriott, Miranda Patterson, Nicola J Curtin, Lauren Averett Byers, Zev A Wainberg
Talazoparib inhibits poly(ADP-ribose) polymerase (PARP) catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this 2-part, phase I, first-in-human trial. Antitumor activity, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%)...
February 27, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28238612/6-benzylidene-2-4-pyridin-3-ylcarboxy-benzylidene-cyclohexanones-a-novel-cluster-of-tumour-selective-cytotoxins
#19
Atulya K Panda, Umashankar Das, Naoki Umemura, Hiroshi Sakagami, Masami Kawase, Jan Balzarini, Erik De Clercq, Stephen G Dimmock, Praveen K Roayapalley, Jonathan R Dimmock
Novel cytotoxins 3-5 containing the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore are disclosed. The compounds in series 3 and 5 have the potential to liberate niacin which may reduce some of the side effects of antineoplastic compounds. 3a-c emerged as the most potent cytotoxic compounds with IC50 values in the low micromolar range against human Molt4/C8 and CEM CD4(+) T-lymphocytes as well as murine L1210 leukemia cells. QSAR studies revealed that cytotoxic potencies were negatively correlated with the magnitude of the Hammett sigma values of the aryl substituents...
April 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28216620/aspirin-alleviates-cardiac-fibrosis-in-mice-by-inhibiting-autophagy
#20
Ping-Ping Liu, Hong-Hong Liu, Shu-Hong Sun, Xing-Xing Shi, Wan-Cheng Yang, Guo-Hai Su, Jing Zhao
Aspirin (ASA) is a cardioprotective drug with anti-cardiac fibrosis action in vivo. This study was aimed to clarify the anti-cardiac fibrosis action of ASA and the underlying mechanisms. Two heart injury models (injection of isoproterenol and ligation of the left anterior descending branch) were used in mice to induce cardiac fibrosis. The animals were treated with ASA (10 mg·kg(-1)·d(-1), ig) for 21 and 14 d, respectively. ASA administration significantly improved cardiac function, and ameliorated heart damage and fibrosis in the mice...
February 20, 2017: Acta Pharmacologica Sinica
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