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poly ADP-ribose polymerase

Chaitanya A Kulkarni, Paul Brookes
<b>Significance:</b> Nicotinamide Adenine Dinucleotide (NAD<sup>+</sup>) spans diverse roles in biology, serving as both an important redox co-factor in metabolism and a substrate for signaling enzymes that regulate protein post-translational modifications (PTMs). <b>Critical Issues:</b> Although the interactions between these different roles of NAD<sup>+</sup> (and its reduced form NADH) have been considered, little attention has been paid to the role of compartmentation in these processes...
February 20, 2019: Antioxidants & Redox Signaling
Jun Shao, Xubin Pan, Xiaowen Yin, Guangming Fan, Chengye Tan, Yong Yao, Yu Xin, Chao Sun
Long noncoding RNAs have been reported to play important roles in the pathogenesis of diabetic retinopathy (DR), which has been considered as the most common disease leading to vision loss. However, it is still unclear whether KCNQ1 overlapping transcript 1 (KCNQ1OT1) could affect DR. In this study, regarding quantitative reverse transcription polymerase chain reaction assay, KCNQ1OT1 level was upregulated while microRNA-1470 (miR-1470) was decreased in DR patients and human retinal endothelial cells. High KCNQ1OT1 expression was correlated with DR stage and low visual function...
February 19, 2019: Journal of Cellular Physiology
Karl Walter Bock
Diverse physiologic functions of AHR, a transcription factor discovered in studies of dioxin toxicity, are currently elucidated in many laboratories including chemical and microbial defense, immunity and myelopoiesis. Accumulating evidence suggests that AHR may also be involved in obesity and TCDD-mediated lethality in sensitive species. Underlying mechanisms include NAD+ - and sirtuin-mediated deregulation of lipid, glucose and NAD+ homeostasis. Progress in NAD metabolome research suggests large consumption of NAD+ by NAD glycohydrolases (NADases) and NAD-dependent sirtuins...
February 16, 2019: Biochemical Pharmacology
Soonyean Hwang, Takayuki Takimoto, Martin E Hemler
Tetraspanin protein CD151 has typically been studied as binding partner and functional regulator of laminin-binding integrins. However, we show here that CD151 supports anti-cancer drug resistance independent of integrins. CD151 ablation sensitized multiple tumor cell types to several anti-cancer drugs (e.g., gefitinib and camptothecin), thus increasing apoptosis, as seen using cleaved caspase-3, cleaved PARP (poly (ADP-ribose) polymerase), annexin V, and propidium iodide staining assays. Drug sensitization due to CD151 ablation is integrin-independent, because, (1) effects occurred in cells when integrins were unengaged with ligand, (2) integrin ablation (α3 and α6 subunits) did not mimic effects of CD151 ablation, (3) the CD151QRD mutant, with diminished integrin association, and CD151WT (unmutated CD151) similarly reconstituted drug protection, and (4) treatment with anti-cancer drugs selectively upregulated intracellular nonintegrin-associated CD151 (NIA-CD151), consistent with its role in drug resistance...
February 18, 2019: Cellular and Molecular Life Sciences: CMLS
Triparna Sen, B Leticia Rodriguez, Limo Chen, Carminia Della Corte, Naoto Morikawa, Junya Fujimoto, Sandra Cristea, Thuyen Nguyen, Lixia Diao, Lerong Li, Youhong Fan, Yongbin Yang, Jing Wang, Bonnie S Glisson, Ignacio I Wistuba, Julien Sage, John V Heymach, Don L Gibbons, Lauren Averett Byers
Despite recent advances in the use of immunotherapy, only a minority of small cell lung cancer (SCLC) patients respond to immune checkpoint blockade (ICB). Here, we show that targeting DNA damage response (DDR) proteins, poly ADP-ribose polymerase (PARP) and checkpoint kinase 1 (CHK1) significantly increased protein and surface expression of PD-L1. PARP or CHK1 inhibition remarkably potentiated the anti-tumor effect of PD-L1 blockade and augmented cytotoxic T-cell infiltration in multiple immunocompetent SCLC in vivo models...
February 18, 2019: Cancer Discovery
Minami Goto, Keishi Owaki, Akihiro Hirata, Tokuma Yanai, Hiroki Sakai
Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is an apoptosis-inducing cytokine that shows potential therapeutic value for human neoplasms, and is effective in some canine tumors; however, its potential for killing canine hemangiosarcoma (HSA) cells is unknown. Thus, we evaluated the proapoptotic effect of TRAIL in nine canine HSA cell lines. Cells (JuA1, JuB2, JuB2-1, JuB4, Re11, Re12, Re21, Ud2, and Ud6) were cultured with three recombinant human TRAILs (rhTRAILs): TRAIL-TEC derived from Escherichia coli, TRAIL-TL derived from mammalian cells, and izTRAIL containing an isoleucine-zippered structure that facilitates trimerization...
February 15, 2019: Veterinary and Comparative Oncology
Eu-Ri Jo, Cha Kyung Youn, Yonghyun Jun, Sung Il Cho
OBJECTIVES: While cisplatin is an effective chemotherapeutic agent, it can cause irreversible hearing loss. Ototoxicity leads to dose reduction during the cisplatin chemotherapy and results in inadequate treatment of malignant tumors. This study aimed to investigate the protective effects of ferulic acid on cisplatin-induced ototoxicity. METHODS: House Ear Institute-Organ of Corti 1 (HEI-OC1) cells were exposed to 30 μM of cisplatin for 24 h with or without pretreatment with ferulic acid...
February 4, 2019: International Journal of Pediatric Otorhinolaryngology
J F Liu, W T Barry, M Birrer, J-M Lee, R J Buckanovich, G F Fleming, B J Rimel, M K Buss, S R Nattam, J Hurteau, W Luo, J Curtis, C Whalen, E C Kohn, S P Ivy, U A Matulonis
Background: Olaparib is a poly(ADP-ribose) polymerase (PARP) inhibitor and cediranib is an oral anti-angiogenic. In the primary analysis of this phase 2 study, combination cediranib/olaparib improved progression-free survival (PFS) compared to olaparib alone in relapsed platinum-sensitive ovarian cancer. This updated analysis was conducted to characterize overall survival (OS) and update PFS outcomes. Patients and Methods: 90 patients were enrolled to this randomized, open-label, phase 2 study between October 2011 and June 2013 across nine United States-based academic centers...
February 7, 2019: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Biljana Cvetanova, Ya-Ching Shen, Lie-Fen Shyur
Mutated proto-oncogene BRAF is a bona fide therapeutic target for melanomas. Regrettably, melanoma acquires resistance to BRAF inhibitors, e.g., vemurafenib (PLX4032) casting doubt on this promising melanoma targeted therapy. In this study, we explored the bioactivity of triterpenoid saponin cumingianoside A (CUMA), isolated from leaves and twigs of Dysoxylum cumingianum against PLX4032-resistant BRAFV 600E mutant melanoma A375-R in vitro and in vivo . Our data show that CUMA treatment inhibited A375-R melanoma cell proliferation in a time- and dose-dependent manner...
2019: Frontiers in Pharmacology
Serena Imperato, Carmela Mistretta, Maria Marone, Ilaria Migliaccio, Ilaria Pulcinelli, Maria Rosaria Faraone Mennella
Increased DNA damage and the propension to cancer development, depend on the modulation of the mechanisms to control and maintain genomic integrity. Poly(ADP-Ribose)Polymerase activation and automodification are early responses to genotoxic stress. Upon binding to DNA strand breaks, the enzyme, a molecular DNA nick sensor, is hyperactivated: this is the first step in a series of events leading to either DNA repair or apoptosis. Enzyme hyperactivation and automodification can be easily measured and are widely used to look at DNA damage extent in the cell...
February 8, 2019: Cells
Erdem Coskun, Gamze Tuna, Pawel Jaruga, Alessandro Tona, Onur Erdem, Miral Dizdaroglu
Poly(ADP ribose) polymerase 1 (PARP1) is a multifunctional DNA repair protein of the base excision repair pathway and plays a major role in the repair of DNA strand breaks and in replication and transcriptional regulation among other functions. Mounting evidence points to the predictive and prognostic value of PARP1 expression in human cancers. Thus, PARP1 has become an important target in cancer therapy, leading to the development of inhibitors as anticancer drugs. In the past, PARP1 expression levels in tissue samples have generally been estimated by indirect and semi-quantitative immunohistochemical methods...
February 1, 2019: DNA Repair
Chunjing Bian, Chao Zhang, Tao Luo, Aditi Vyas, Shih-Hsun Chen, Chao Liu, Muzaffer Ahmad Kassab, Ying Yang, Mei Kong, Xiaochun Yu
ADP-ribosylation is a unique posttranslational modification catalyzed by poly(ADP-ribose) polymerases (PARPs) using NAD+ as ADP-ribose donor. PARPs play an indispensable role in DNA damage repair and small molecule PARP inhibitors have emerged as potent anticancer drugs. However, to date, PARP inhibitor treatment has been restricted to patients with BRCA1/2 mutation-associated breast and ovarian cancer. One of the major challenges to extend the therapeutic potential of PARP inhibitors to other cancer types is the absence of predictive biomarkers...
February 11, 2019: Nature Communications
Zehua Wang, Jianwen Gao, Jiabing Zhou, Haiou Liu, Congjian Xu
OBJECTIVE: Poly (ADP-ribose) polymerase (PARP) is an important molecule in the early stress response of DNA damage, which is involved in DNA damage repair and cellular senescence. Olaparib, as PARP inhibitor, has an anti-tumor effect on high grade serous ovarian cancer, but its effects on cellular senescence have not been reported. This study intends to explore the role of olaparib in the regulation of senescence in ovarian cancer cells. METHODS: The effects of olaparib on the senescence of ovarian cancer cells were detected by using the senescence-associated β-galactosidase (SA-β-Gal) and senescence-associated heterochromatin aggregation (SAHF)...
November 22, 2018: Journal of Gynecologic Oncology
Yuma Nonomiya, Kohji Noguchi, Kazuhiro Katayama, Yoshikazu Sugimoto
Poly (ADP-ribose) polymerases (PARPs) are involved in various cellular events, including DNA repair. PARP inhibitors including olaparib and rucaparib, have been specially developed against breast and ovarian cancers deficient in DNA repair systems. In this study, we found that PARP1-defective olaparib-resistant A2780 cells (ola-R cells) cells were still sensitive to two PARP inhibitors, rucaparib and veliparib. Metabolomic analysis revealed that rucaparib suppressed the lactate dehydrogenase (LDH)-mediated conversion of pyruvic acid to lactic acid in A2780 cells, although olaparib did not...
February 5, 2019: Biochemical and Biophysical Research Communications
Jining Yang, Xi Zhou, Xianglong Zeng, Ou Hu, Long Yi, Mantian Mi
Background/aims: Oxidative stress-induced damage in endothelial cells is a crucial initiator of atherosclerosis (AS), which is highly related to excessive reactive oxygen species (ROS) and mitochondrial dynamics. Resveratrol (RSV) exerts beneficial effects against endothelial oxidative injury, while the underlying mechanisms have not been fully elucidated. Thus, we aimed to explore the role of mitochondria dynamics during the anti-oxidative activities of RSV in palmitic acid (PA)-stimulated human umbilical vein endothelial cells (HUVECs) and to verify whether tyrosyl transfer- RNA synthetase (TyrRS) and poly (ADP-ribose) polymerase 1 (PARP1) are targeted during this process...
2019: Nutrition & Metabolism
William Bain, Tolani Olonisakin, Minting Yu, Yanyan Qu, Mei Hulver, Zeyu Xiong, Huihua Li, Joseph Pilewski, Rama K Mallampalli, Mehdi Nouraie, Anuradha Ray, Prabir Ray, Zhenyu Cheng, Robert M Q Shanks, Claudette St Croix, Roy L Silverstein, Janet S Lee
Thrombocytopenia is associated with worse outcomes in patients with acute respiratory distress syndrome, which is most commonly caused by infection and marked by alveolar-capillary barrier disruption. However, the mechanisms by which platelets protect the lung alveolar-capillary barrier during infectious injury remain unclear. We found that natively thrombocytopenic Mpl -/- mice deficient in the thrombopoietin receptor sustain severe lung injury marked by alveolar barrier disruption and hemorrhagic pneumonia with early mortality following acute intrapulmonary Pseudomonas aeruginosa (PA) infection; barrier disruption was attenuated by platelet reconstitution...
February 12, 2019: Blood Advances
Feifei Wang, Songli Zhu, Laura A Fisher, Ling Wang, Nicholas J Eurek, James K Wahl, Li Lan, Aimin Peng
Poly (ADP-ribose) polymerases (PARP), particularly PARP1, play an essential role in the detection and repair of DNA single strand breaks (SSB) and double strand breaks (DSB). PARP1 accumulates at DNA damage sites within seconds after DNA damage to catalyze the massive induction of substrate protein poly ADP-ribosylation (PARylation). However, the molecular mechanisms underlying the recruitment and activation of PARP1 in DNA repair are not fully understood. Here we show that PNUTS is a robust binding partner of PARP1...
February 7, 2019: Cancer Research
Qiang Zhang, Ahmed S A Mady, Yuanyuan Ma, Caila Ryan, Theodore S Lawrence, Zaneta Nikolovska-Coleska, Yi Sun, Meredith A Morgan
FBXW7, a classic tumor suppressor, is a substrate recognition subunit of the Skp1-cullin-F-box (SCF) ubiquitin ligase that targets oncoproteins for ubiquitination and degradation. We recently found that FBXW7 is recruited to DNA damage sites to facilitate nonhomologous end-joining (NHEJ). The detailed underlying molecular mechanism, however, remains elusive. Here we report that the WD40 domain of FBXW7, which is responsible for substrate binding and frequently mutated in human cancers, binds to poly(ADP-ribose) (PAR) immediately following DNA damage and mediates rapid recruitment of FBXW7 to DNA damage sites, whereas ATM-mediated FBXW7 phosphorylation promotes its retention at DNA damage sites...
February 5, 2019: Nucleic Acids Research
J Fuller, R A Surtees, A B Shaw, B Álvarez-Rodríguez, G S Slack, Lesley Bell-Sakyi, J Mankouri, T A Edwards, R Hewson, J N Barr
The Nairoviridae family within the Bunyavirales order comprise tick-borne segmented negative-sense RNA viruses that cause serious disease in a broad range of mammals, yet cause a latent and lifelong infection in tick hosts. An important member of this family is Crimean-Congo haemorrhagic fever virus (CCHFV), which is responsible for serious human disease that results in case fatality rates of up to 30 %, and which exhibits the most geographically broad distribution of any tick-borne virus. Here, we explored differences in the cellular response of both mammalian and tick cells to nairovirus infection using Hazara virus (HAZV), which is a close relative of CCHFV within the CCHFV serogroup...
February 5, 2019: Journal of General Virology
Annalisa Masi, Arianna Sabbia, Carla Ferreri, Francesco Manoli, Yanhao Lai, Eduardo Laverde, Yuan Liu, Marios G Krokidis, Chryssostomos Chatgilialoglu, Maria Rosaria Faraone Mennella
5',8-Cyclo-2'-deoxyadenosine (cdA), in the 5' R and 5' S diastereomeric forms, are typical non strand-break oxidative DNA lesions, induced by hydroxyl radicals, with emerging importance as a molecular marker. These lesions are exclusively repaired by the nucleotide excision repair (NER) mechanism with a low efficiency, thus readily accumulating in the genome. Poly(ADP-ribose) polymerase1 (PARP1) acts as an early responder to DNA damage and plays a key role as a nick sensor in the maintenance of the integrity of the genome by recognizing nicked DNA...
February 2, 2019: Cells
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