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poly ADP-ribose polymerase

Zafeiris Zafeiriou, Diletta Bianchini, Robert Chandler, Pasquale Rescigno, Wei Yuan, Suzanne Carreira, Maialen Barrero, Antonella Petremolo, Susana Miranda, Ruth Riisnaes, Daniel Nava Rodrigues, Bora Gurel, Semini Sumanasuriya, Alec Paschalis, Adam Sharp, Joaquin Mateo, Nina Tunariu, Arul M Chinnaiyan, Colin C Pritchard, Kevin Kelly, Johann S de Bono
Platinum-based regimens have not been proved to increase survival from advanced prostate cancer (PCa). Incontrovertible evidence that a proportion of prostate cancers have homologous recombination DNA (HRD) repair defects, and that such genomic aberrations are synthetically lethal with both poly(ADP)-ribose polymerase inhibition and platinum, has increased interest in the utilisation of these drugs against a subset of these diseases. Here in we report three patients with advanced castration-resistant PCa with HRD defects having exceptional responses to carboplatin...
October 16, 2018: European Urology
Ji-Young Seok, Yun-Jeong Jeong, Soon-Kyung Hwang, Cheorl-Ho Kim, Junji Magae, Young-Chae Chang
4-O-methylascochlorin (MAC) is a derivative of ascochlorin, a prenyl-phenol compound antibiotic isolated from the fungus Ascochyta viciae. MAC induces caspase/poly (ADP-ribose) polymerase-mediated apoptosis in leukemia cells. However, the effects of MAC on autophagy in cancer cells and the underlying molecular mechanisms remain unknown. Here, we show that MAC induces autophagy in lung cancer cells. MAC significantly induced the expression of autophagy marker proteins including LC3-II, Beclin1, and ATG7. MAC promoted AMP-activated protein kinase (AMPK) phosphorylation and inhibited the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream signalling proteins P70S6K and 4EBP1...
October 19, 2018: Journal of Cellular and Molecular Medicine
Hye Rim Suh, Eui Ho Park, Sun Wook Moon, Ji Won Kim, Hwi Young Cho, Hee Chul Han
INTRODUCTION: Lengthened immobilization may prevent muscle shortening, and help maintain normal muscle length. However, its apoptotic effects remain unclear. We evaluated the effects of long-term immobilization on apoptotic proteins. METHODS: Rat soleus muscles were immobilized by casting in a neutral (NEUT) or lengthened (LENG) position for 21 days. We evaluated dynamic weight load and muscle atrophy following the 21-day period using hematoxylin and eosin staining...
October 19, 2018: Muscle & Nerve
Jae Sik Yu, Hyun-Soo Roh, Kwan-Hyuck Baek, Seul Lee, Sil Kim, Hae Min So, Eunjung Moon, Changhyun Pang, Tae Su Jang, Ki Hyun Kim
Background: Lung cancer is the leading cause of cancer-related death worldwide. In this study, we used a bioactivity-guided isolation technique to identify constituents of Korean Red Ginseng (KRG) with antiproliferative activity against human lung adenocarcinoma cells. Methods: Bioactivity-guided fractionation and preparative/semipreparative HPLC purification were used with LC/MS analysis to separate the bioactive constituents. Cell viability and apoptosis in human lung cancer cell lines (A549, H1264, H1299, and Calu-6) after treatment with KRG extract fractions and constituents thereof were assessed using the water-soluble tetrazolium salt (WST-1) assay and terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, respectively...
October 2018: Journal of Ginseng Research
J Sun, W D Song, S Y Yan, Z J Xi
OBJECTIVE: To determine whether chloroquine (CQ), an often used inhibitor of late autophagy and autophagosome/lyosome fusion, can inhibit proliferation of renal carcinoma cells and investigate its effect on sunitinib (ST)-induced apoptosis. METHODS: Renal carcinoma cell line 786 O and ACHN had been used as cellular model and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay was carried out to detect the cell viability in response to CQ or ST treatment...
October 18, 2018: Beijing da Xue Xue Bao. Yi Xue Ban, Journal of Peking University. Health Sciences
You-Dong Zhou, Li Cai
BACKGROUND: Inhibition of calpain activity provides neuroprotection in multiple central nervous system injury, but the role and mechanism of calpain in subarachnoid hemorrhage (SAH) remain unclear. This study was undertaken to determine the effects of inhibition of calpain on neurological deficit and neuronal apoptosis following experimental SAH. METHODS: The endovascular perforation model of SAH was produced in male Sprague-Dawley rats. Rats were administered calpeptin 50μg, intracerebroventricular injection, 30 minutes before induction of SAH...
October 15, 2018: Journal of Stroke and Cerebrovascular Diseases: the Official Journal of National Stroke Association
Neha Sharma, Lisamarie Moore, Shravanthi Chidambaram, Nicholas W Colangelo, Sonia M de Toledo, Edouard I Azzam
Neural stem cells are attracting enormous attention in regenerative medicine due to their ability to self-renew and differentiate into the cell lineages that constitute the central nervous system. However, little is known about the mechanism underlying the regulation of their redox environment, which is essential for homeostatic cellular functions. The redox-modulated c-Jun N-terminal kinases (JNK) are a molecular switch in stress signal transduction and are involved in numerous brain functions. Using a selective but broad-spectrum inhibitor of JNK 1/2/3, we investigated the role of JNK in regulating the levels of reactive oxygen species in mitochondria, mitochondrial membrane potential, viability, proliferation and lineage alterations in human H9-derived neural stem/progenitor cells (NSPs)...
October 18, 2018: Developmental Neuroscience
Haicong Chen, Zhaojun Wang, Xin Wang, Zhen Guo, Zhujin Xu, Yi Zhao, Jiashang Cai, Jun Liu
In the present study, a polysaccharide (ECP) from Enterobacter cloacae dose and time-dependently inhibited cell growth of human osteosarcoma U-2 OS cells via induction of apoptosis. ECP treatment was selectively toxic to U-2 OS cells whereas had no cytotoxic effect on normal human osteoblast cell line NHOst. ECP-induced apoptotic cell death was associated with collapse of mitochondrial membrane, cytochrome c release into the cytosol, activation of caspase-9 and-3, degradation of poly (ADP-ribose) polymerase (PARP), elevated the ratio of Bax/Bcl-2 protein and overexpression of p53, suggesting the involvement of the activation of p53 and mitochondrial intrinsic pathway in ECP-induced apoptosis...
October 15, 2018: International Journal of Biological Macromolecules
Gabor Liposits, Kah Poh Loh, Enrique Soto-Perez-de-Celis, Lucy Dumas, Nicolò Matteo Luca Battisti, Sindhuja Kadambi, Capucine Baldini, Susana Banerjee, Stuart M Lichtman
Breast and ovarian cancer are common malignancies among older adults, causing significant morbidity and mortality. Although most cases of breast and ovarian cancer are sporadic, a significant proportion is caused by mutations in cancer susceptibility genes, most often breast cancer susceptibility genes (BRCA) 1 and 2. Furthermore, some breast and ovarian tumors are phenotypically similar to those with BRCA mutations, a phenomenon known as "BRCAness". BRCA mutations and "BRCAness" lead to defects in DNA repair, which may be a target for therapeutic agents such as Poly ADP-Ribose Polymerase (PARP) inhibitors...
October 14, 2018: Journal of Geriatric Oncology
Mahwish Khan, Zeeshan Shaukat, Robert Saint, Stephen L Gregory
Aneuploidy - - having an unbalanced genome - is poorly tolerated at the cellular and organismal level. It gives rise to proteotoxic stress as well as a stereotypical oxidative shift which makes these cells sensitive to internal and environmental stresses. Using Drosophila as a model, we found that protein folding stress is exacerbated by redox stress that occurs in response to ongoing changes to ploidy (chromosomal instability, CIN). We also found that if de novo nucleotide synthesis is blocked, CIN cells are dependent on a high level of lysosome function to survive...
October 16, 2018: Biology Open
H Ramamoorthy, P Abraham, B Isaac, D Selvakumar
Tenofovir disoproxil fumarate (TDF) is currently the only nucleotide analogue reverse-transcriptase inhibitor that is approved by the Food and Drug administration (FDA), USA, for the treatment of human immunodeficiency virus (HIV) infection. In recent days, renal toxicity is becoming common i HIV patients treated with TDF. However, the mechanism of tenofovir nephrotoxicity is not clear. We hypothesized that mitochondrial pathway of apoptosis, poly [ADP-ribose] polymerase (PARP) overactivation and neutrophil infiltration may contribute to tenofovir-induced renal damage...
October 16, 2018: Human & Experimental Toxicology
Rohit Gundamaraju, Ravichandra Vemuri, Wai Chin Chong, Stephen Myers, Shaghayegh Norouzi, Madhur D Shastri, Rajaraman Eri
Sustained endoplasmic reticular stress (ERS) is implicated in aggressive metastasis of cancer cells and increased tumor cell proliferation. Cancer cells activate the unfolded protein response (UPR), which aids in cellular survival and adaptation to harsh conditions. Inhibition of apoptosis, in contrast, is a mechanism adopted by cancer cells with the help of the inhibitor of an apoptosis (IAP) class of proteins such as Survivin to evade cell death and gain a proliferative advantage. In this study, we aimed to reveal the interrelation between ERS and Survivin...
October 15, 2018: Cells
Se Hyun Kim, Haram Ryu, Chan-Young Ock, Koung Jin Suh, Ji Yun Lee, Ji-Won Kim, Jeong-Ok Lee, Jin Won Kim, Yu Jung Kim, Keun-Wook Lee, Soo-Mee Bang, Jee Hyun Kim, Jong Seok Lee, Joong Bae Ahn, Kui-Jin Kim, Sun Young Rha
Paclitaxel (PTX) is commonly used to treat urothelial carcinoma (UC) after platinum-based chemotherapy has failed. However, single-agent taxane therapy is not sufficient to inhibit tumor progression and drug resistance in advanced UC. Epithelial-to-mesenchymal transition (EMT) induced by fibroblast growth factor receptor ( FGFR )1 signaling has been proposed as a mechanism of PTX resistance, but it is unclear whether this can be overcome by FGFR1 inhibition. The present study investigated whether FGFR1 overexpression contributes to PTX resistance and whether FGFR inhibition can enhance PTX efficacy in UC...
October 15, 2018: International Journal of Molecular Sciences
Monika Pospisilova, Martin Andrs, Martina Seifrtova, Radim Havelek, Daniel Jun, Pavel Tomsik, Lukas Prchal, Rafael Dolezal, Ales Tichy, Tomas Kucera, Jan Korabecny, Martina Rezacova
We report the design, synthesis and biological evaluation of 17 novel 8-aryl-2-morpholino-3,4-dihydroquinazoline derivatives based on the standard model of DNA-PK and PI3K inhibitors. Novel compounds are sub-divided into two series where the second series of five derivatives was designed to have a better solubility profile over the first one. A combination of in vitro and in silico techniques suggested a plausible synergistic effect with doxorubicin of the most potent compound 14d on cell proliferation via DNA-PK and poly(ADP-ribose) polymerase-1 (PARP-1) inhibition, while alone having a negligible effect on cell proliferation...
October 6, 2018: Bioorganic Chemistry
Cheng Wang, Wenjing Xu, Yanqing Zhang, Fengxiao Zhang, Kai Huang
Autophagy is a key regulatory process in maintaining cellular homoeostasis via lysosome degradation. Growing evidence reveals that poly(ADP-ribose) polymerase-1 (PARP1) is involved in the progression of many cardiovascular diseases. This study was undertaken to discuss the role of PARP1 in cardiomyocyte autophagy. Our results demonstrated that PARP1 was activated in response to starvation-induced myocardial autophagy. We identified Forkhead box O (FoxO)3a as a substrate of PARP1. Upon PARP1 activation, poly(ADP-ribosyl)ation dissociated histone H1 from FoxO3a target gene promoter and promoted FoxO3a nuclear accumulation and binding activity to the target promoters, resulting in increased expression of autophagy related genes...
October 15, 2018: Cell Death & Disease
Rachy Abraham, Debra Hauer, Robert Lyle McPherson, Age Utt, Ilsa T Kirby, Michael S Cohen, Andres Merits, Anthony K L Leung, Diane E Griffin
Alphaviruses are plus-strand RNA viruses that cause encephalitis, rash, and arthritis. The nonstructural protein (nsP) precursor polyprotein is translated from genomic RNA and processed into four nsPs. nsP3 has a highly conserved macrodomain (MD) that binds ADP-ribose (ADPr), which can be conjugated to protein as a posttranslational modification involving transfer of ADPr from NAD+ by poly ADPr polymerases (PARPs). The nsP3MD also removes ADPr from mono ADP-ribosylated (MARylated) substrates. To determine which aspects of alphavirus replication require nsP3MD ADPr-binding and/or hydrolysis function, we studied NSC34 neuronal cells infected with chikungunya virus (CHIKV)...
October 15, 2018: Proceedings of the National Academy of Sciences of the United States of America
Inna A Vasil'eva, Rashid O Anarbaev, Nina A Moor, Olga I Lavrik
Base excision repair (BER) involves many enzymes acting in a coordinated fashion at the most common types of DNA damage. The coordination is facilitated by interactions between the enzymes and accessory proteins, X-ray repair cross-complementing protein 1 (XRCC1) and poly(ADP-ribose) polymerase 1 (PARP1). Here we use dynamic light scattering (DLS) technique to determine the hydrodynamic sizes of several BER enzymes and proteins, DNA polymerase β (Polβ), apurinic/apyrimidinic endonuclease 1 (APE1), tyrosyl-DNA phosphodiesterase 1 (TDP1), XRCC1 and PARP1, present alone or in the equimolar mixtures with each other...
October 12, 2018: Biochimica et biophysica acta. Proteins and proteomics
Özge Rencüzoğullari, Elif Damla Arısan, Pinar Obakan Yerlikaya, Ajda Çoker Gürkan, Buse Keskin, Narçin Palavan Ünsal
Purvalanol and roscovitine are specific cyclin-dependent kinase (CDK) inhibitors, which have antiproliferative and apoptotic effects on various types of cancer. Although, the apoptotic accomplishment of purvalanol and roscovitine was elucidated at the molecular level, the underlying exact of drug-induced apoptosis through mitogen-activated protein kinase (MAPK) signaling still speculative. In addition, the role of CDK inhibitors in the downregulation of extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated epithelial-mesenchymal transition (EMT) remains unclear...
October 15, 2018: Journal of Cellular Biochemistry
Jai N Patel, Ioana Braicu, Kirsten M Timms, Cara Solimeno, Placede Tshiaba, Julia Reid, Jerry S Lanchbury, Silvia Darb-Esfahani, Mahrukh K Ganapathi, Jalid Sehouli, Ram N Ganapathi
BACKGROUND: Homologous recombination deficiency (HRD) is shown to predict response to DNA-damaging therapies in patients with high-grade serous ovarian cancer (HGSOC); however, changes in HRD during progression remains unknown. METHODS: HRD scores were evaluated in paired primary and/or recurrent HGSOC samples (N = 107) from 54 patients with adjuvant platinum-based chemotherapy. BRCA1/2 mutation, BRCA1 methylation, loss of heterozygosity (LOH), and HRD scores were characterised using tumour DNA-based next-generation sequencing assays...
October 15, 2018: British Journal of Cancer
Tina Jubin, Ashlesha Kadam, Shweta Saran, Rasheedunnisa Begum
The unicellular, as well as multicellular stages of Dictyostelium discoideum's life cycle, make it an excellent model system for cell type determination, differentiation, development, and cell death studies. Our preliminary results show the involvement of poly (ADP-ribose) polymerase-1 (PARP-1) during D. discoideum growth by its constitutive downregulation as well as by its ortholog overexpression. The current study now analyzes and strengthens the role of the PARP-1 ortholog in cellular proliferation of D...
October 14, 2018: Journal of Cellular Physiology
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