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https://www.readbyqxmd.com/read/28340412/discovery-of-2-substituted-1h-benzo-d-immidazole-4-carboxamide-derivatives-as-novel-poly-adp-ribose-polymerase-1-inhibitors-with-in%C3%A2-vivo-anti-tumor-activity
#1
Jie Zhou, Ming Ji, Zhixiang Zhu, Ran Cao, Xiaoguang Chen, Bailing Xu
Novel 1H-benzo[d]immidazole-4-carboxamide derivatives bearing five-membered or six-membered N-heterocyclic moieties at the 2-position were designed and synthesized as PARP-1 inhibitors. Structure-activity relationships were conducted and led to a number of potent PARP-1 inhibitors having IC50 values in the single or double digit nanomolar level. Some potent PARP-1 inhibitors also had similar inhibitory activities against PARP-2. Among all the synthesized compounds, compound 10a and 11e displayed strong potentiation effects on temozolomide (TMZ) in MX-1 cells (PF50 = 7...
March 18, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28339485/chronic-parp-1-inhibition-reduces-carotid-vessel-remodeling-and-oxidative-damage-of-the-dorsal-hippocampus-in-spontaneously-hypertensive-rats
#2
Krisztian Eros, Klara Magyar, Laszlo Deres, Arpad Skazel, Adam Riba, Zoltan Vamos, Tamas Kalai, Ferenc Gallyas, Balazs Sumegi, Kalman Toth, Robert Halmosi
Vascular remodeling during chronic hypertension may impair the supply of tissues with oxygen, glucose and other compounds, potentially unleashing deleterious effects. In this study, we used Spontaneously Hypertensive Rats and normotensive Wistar-Kyoto rats with or without pharmacological inhibition of poly(ADP-ribose)polymerase-1 by an experimental compound L-2286, to evaluate carotid artery remodeling and consequent damage of neuronal tissue during hypertension. We observed elevated oxidative stress and profound thickening of the vascular wall with fibrotic tissue accumulation induced by elevated blood pressure...
2017: PloS One
https://www.readbyqxmd.com/read/28337869/knockdown-of-hmgb1-inhibits-cell-proliferation-and-induces-apoptosis-in-hemangioma-via-downregulation-of-akt-pathway
#3
C Pan, Y Wang, M K Qiu, S Q Wang, Y B Liu, Z W Quan, J M Ou
The high mobility group box 1 (HMGB1) as a conserved non-histone nuclear protein has been involved in a variety of biological processes of cancer, such as cell proliferation, apoptosis, angiogenesis and metastasis. Despite the increased expression of HMGB1 in many malignant tumors, the functions and molecular mechanisms by which HMGB1 contributes to the formation of hemangioma (HA) remain unclear. In the present study, immunohistochemistry was used to detect the expression levels of HMGB1 in different phases of human HAs...
January 2017: Journal of Biological Regulators and Homeostatic Agents
https://www.readbyqxmd.com/read/28337703/umi-77-primes-glioma-cells-for-trail-induced-apoptosis-by-unsequestering-bim-and-bak-from-mcl-1
#4
Ji-Wei Liu, Zhi-Chuan Zhu, Kui Li, Hong-Tao Wang, Zhi-Qi Xiong, Jing Zheng
Malignant glioma is the most common and aggressive form of brain tumor with poor prognosis of survival. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent but is insufficient of inducing apoptosis in some types of gliomas. In this study, we showed that the small-molecule Mcl-1 inhibitor UMI-77 sensitized glioma cells to TRAIL treatment, as evidenced by cell viability assay, Annexin V staining and JC-1 staining. Combination of UMI-77 and TRAIL in glioma cells led to the activation of caspase-8 and Bid, cleavage of caspase-3 and poly-ADP ribose polymerase (PARP), accumulation of tBid in the mitochondria and release of cytochrome c into the cytosol...
March 23, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28337255/combined-therapy-with-melatonin-and-exendin-4-effectively-attenuated-the-deterioration-of-renal-function-in-rat-cardiorenal-syndrome
#5
Kuan-Hung Chen, Chih-Hung Chen, Christopher Glenn Wallace, Yen-Ta Chen, Chih-Chao Yang, Pei-Hsun Sung, Hsin-Ju Chiang, Yi-Ling Chen, Sarah Chua, Hon-Kan Yip, Jiin-Tsuey Cheng
This study tested the hypothesis that combined therapy with melatonin (Mel) and exendin-4 (Ex4) would be superior to either therapy alone for preventing the deterioration of renal function in cardiorenal syndrome (CRS). Male adult Sprague Dawley rats (n = 48) were randomly and equally divided into sham-control (SC), chronic kidney disease (CKD; induced by 5/6 nephrectomy), CRS (CKD + dilated cardiomyopathy, DCM; induced by doxorubicin 7 mg/kg i.p. every 5 days, 4 doses), CRS-Mel (20 mg/kg/day), CRS-Ex4 (10 µg/kg/day) and CRS-Mel-Ex4...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28323499/antiproliferative-activity-of-egg-yolk-peptides-in-human-colon-cancer-cells
#6
Marwa N Yousr, Akram A Aloqbi, Ulfat M Omar, Nazlin K Howell
Egg yolk peptides were successfully prepared from egg yolk protein by-products after lecithin extraction. Defatted egg yolk protein was hydrolyzed with pepsin and pancreatin and purified by gel filtration to produce egg yolk gel filtration fraction (EYGF-33) with antiproliferative activity. The highlight of this study was that the peptide EYGF-33 (1.0 mg/ml) significantly inhibits cell viability of colon cancer cells (Caco-2) with no inhibitory effects on the viability of human colon epithelial normal cells (HCEC) after 48 h...
March 21, 2017: Nutrition and Cancer
https://www.readbyqxmd.com/read/28322842/simultaneous-blockade-of-nmda-receptors-and-parp-1-activity-synergistically-alleviate-immunoexcitotoxicity-and-bioenergetics-in-3-nitropropionic-acid-intoxicated-mice-evidences-from-memantine-and-3-aminobenzamide-interventions
#7
Saravana Babu Chidambaram, Ranju Vijayan, Sathiya Sekar, Sugumar Mani, Barathidsan Rajamani, Ramakrishnan Ganapathy
Interlink between excitotoxicity and cellular bioenergetics depletion is implicated as one of the central deteriorative pathways in many neurodegenerative diseases including Huntington's disease (HD). Chronic administration of 3-nitropropionic acid (3-NP) depletes ATP and NAD(+;) and increases TNFα, IL-6 and glutamate content resulting in "immunoexcitotoxicity". Present study was designed to determine whether the combination of memantine (MN) and 3-aminobenzamide (3-AB), PARP inhibitor, can ameliorate immunoexcitotoxicity and improve bioenergetics in a better manner than individual administration against 3-NP intoxication in mice...
March 16, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28322340/signalling-mechanisms-mediating-zn-2-induced-trpm2-channel-activation-and-cell-death-in-microglial-cells
#8
Sharifah Syed Mortadza, Joan A Sim, Martin Stacey, Lin-Hua Jiang
Excessive Zn(2+) causes brain damage via promoting ROS generation. Here we investigated the role of ROS-sensitive TRPM2 channel in H2O2/Zn(2+)-induced Ca(2+) signalling and cell death in microglial cells. H2O2/Zn(2+) induced concentration-dependent increases in cytosolic Ca(2+) concentration ([Ca(2+)]c), which was inhibited by PJ34, a PARP inhibitor, and abolished by TRPM2 knockout (TRPM2-KO). Pathological concentrations of H2O2/Zn(2+) induced substantial cell death that was inhibited by PJ34 and DPQ, PARP inhibitors, 2-APB, a TRPM2 channel inhibitor, and prevented by TRPM2-KO...
March 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28321485/initial-autophagic-protection-switches-to-disruption-of-autophagic-flux-by-lysosomal-instability-during-cadmium-stress-accrual-in-renal-nrk-52e-cells
#9
W-K Lee, S Probst, M P Santoyo-Sánchez, W Al-Hamdani, I Diebels, J-K von Sivers, E Kerek, E J Prenner, F Thévenod
The renal proximal tubule (PT) is the major target of cadmium (Cd(2+)) toxicity where Cd(2+) causes stress and apoptosis. Autophagy is induced by cell stress, e.g., endoplasmic reticulum (ER) stress, and may contribute to cell survival or death. The role of autophagy in Cd(2+)-induced nephrotoxicity remains unsettled due to contradictory results and lack of evidence for autophagic machinery damage by Cd(2+). Cd(2+)-induced autophagy in rat kidney PT cell line NRK-52E and its role in cell death was investigated...
March 20, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28316571/anti-cancerous-potential-of-polysaccharide-fractions-extracted-from-peony-seed-dreg-on-various-human-cancer-cell-lines-via-cell-cycle-arrest-and-apoptosis
#10
Fang Zhang, Jun-Jun Shi, Kiran Thakur, Fei Hu, Jian-Guo Zhang, Zhao-Jun Wei
In this study, four homo/heterogenous polysaccharides (HBSS, CHSS, DASS, and CASS) extracted from peony seed dreg with respective molecular weights of 3467, 4677, 229, and 56 kDa were evaluated for anti-cancerous attributes in prostate cancer cells (Pc-3), colon cancer cells (HCT-116), human breast cancer cells (MCF-7), cervical cancer (Hela cells) and human embryonic kidney 293 (HEK 293) cells as control. Among them, CASS and DASS extracted by alkali, consisted of 34.43% Gal, 26.39% Ara, 21.80% Glc and 35...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28316110/proteasome-ubiquitin-receptor-psmd4-is-an-amplification-target-in-breast-cancer-and-may-predict-sensitivity-to-parpi
#11
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/28315428/p53-modulates-the-effect-of-ribosomal-protein-s6-kinase1-s6k1-on-cisplatin-toxicity-in-chronic-myeloid-leukemia-cells
#12
Ling-Yi Xiao, Wai-Ming Kan
Chronic myeloid leukemia (CML) is characterized by the expression of the oncoprotein, BCR-ABL. BCR-ABL inhibitors revolutionized CML chemotherapy while blast crisis (BC) CML patients are less responsive. Since suppression of ribosomal protein S6 kinase1 (S6K1) phosphorylation reverses the resistance to BCR-ABL inhibitor in CML cells and S6K1 inhibitors augment cisplatin toxicity in lung cancer cells, we speculated that combination of S6K1 inhibitor and cisplatin may be beneficial for eliminating BC CML cells...
March 14, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28314788/the-parp-inhibitor-veliparib-can-be-safely-added-to-bendamustine-and-rituximab-and-has-preliminary-evidence-of-activity-in-b-cell-lymphoma
#13
Jacob D Soumerai, Andrew D Zelenetz, Craig Moskowitz, M Lia Palomba, Paul A Hamlin, Ariela Noy, David J Straus, Alison J Moskowitz, Anas Younes, Matthew J Matasar, Steven Horwitz, Carol Portlock, Jason Konner, Mrinal M Gounder, David M Hyman, Martin H Voss, Matthew G Fury, Devika Gajria, Richard D Carvajal, Alan L Ho, Jan H Beumer, Brian Kiesel, Zhigang Zhang, Alice Chen, Richard F Little, Christine Jarjies, Thu O Dang, Fallon France, Nishant Mishra, John F Gerecitano
PURPOSE: The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. This phase 1 study evaluated veliparib with the bifunctional alkylator bendamustine (VB) in patients with relapsed/refractory lymphoma, multiple myeloma, and solid malignancies, with a cohort expansion of VB with rituximab (VBR) in patients with B-cell lymphomas. EXPERIMENTAL DESIGN: This dose-escalation study evaluated safety, pharmacokinetics and preliminary efficacy of veliparib (20-400 mg BID, days 1-7 of 28-day cycle) and bendamustine (70 and 90 mg/m2 IV, days 1 and 2)...
March 17, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28303528/human-mass-balance-study-and-metabolite-profiling-of-14-c-niraparib-a-novel-poly-adp-ribose-polymerase-parp-1-and-parp-2-inhibitor-in-patients-with-advanced-cancer
#14
Lotte van Andel, Z Zhang, S Lu, V Kansra, S Agarwal, L Hughes, M M Tibben, A Gebretensae, L Lucas, M J X Hillebrand, H Rosing, J H M Schellens, J H Beijnen
Niraparib is an investigational oral, once daily, selective poly(ADP-Ribose) polymerase (PARP)-1 and PARP-2 inhibitor. In the pivotal Phase 3 NOVA/ENGOT/OV16 study, niraparib met its primary endpoint of improving progression-free survival (PFS) for adult patients with recurrent, platinum sensitive, ovarian, fallopian tube, or primary peritoneal cancer in complete or partial response to platinum-based chemotherapy. Significant improvements in PFS were seen in all patient cohorts regardless of biomarker status...
March 16, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28302009/expression-and-single-nucleotide-polymorphism-of-poly-adp-ribose-polymerase-1-in-gastrointestinal-tumours-clinical-involvement
#15
Sandra María Martín-Guerreroa, Josefa Leóna, Rosa Quiles-Pereza, Laura Belmontee, David Martin-Olivaa, Ángeles Ruiz-Extremeraa, Javier Salmeróna, José Antonio Muñoz-Gámez
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that plays a critical role in diverse cellular functions, such as DNA damage detection and repair, transcriptional regulation and cell death. Furthermore, PARP-1 has emerged as a key player in the pathogenesis of multiple inflammatory diseases and has become a promising target for the treatment of cardiovascular disorders, neurodegenerative diseases and cancer. An increasing body of evidence has linked alterations in the expression levels of PARP-1, enzymatic activity and presence of polymorphism to gastrointestinal malignancies, including oesophageal, gastric, pancreas, liver and colorectal cancers...
March 16, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28301380/nitroxoline-shows-antimyeloma-activity-by-targeting-the-trim25-p53-axle
#16
Hongwu Mao, Yanyun Du, Zubin Zhang, Biyin Cao, Jun Zhao, Haibin Zhou, Xinliang Mao
The aim of this study was to identify the most potent quinoline-based anti-infectives for the treatment of multiple myeloma (MM) and to understand the molecular mechanisms. A small-scale screen against a panel of marketed quinoline-based drugs was performed in MM cell lines. Cell apoptosis was examined by flow cytometry. Anti-MM activity was also evaluated in nude mice. Western blotting was performed to investigate mechanisms. Nitroxoline (NXQ) was the most effective in suppressing MM cell proliferation. NXQ induced more than 40% MM cell apoptosis within 24 h and potentiated anti-MM activities of current major drugs including doxorubicin and lenalidomide...
April 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28299955/niraparib-for-the-treatment-of-ovarian-cancer
#17
Yada Kanjanapan, Stephanie Lheureux, Amit M Oza
Introduction Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are being developed in maintenance and recurrence treatment settings in ovarian cancer. They inhibit single-stranded DNA repair, inducing synthetic lethality in cells with underlying homologous recombination deficiency (HRD). Marked responses are seen in ovarian cancers with breast cancer gene 1 (BRCA1) or 2 (BRCA2) mutation, although up to 50% of high-grade serous ovarian cancers (HGSOC) have HRD may also benefit. Areas covered This review focuses on niraparib (oral PARP I and II inhibitor), its clinical testing in ovarian cancer, including the Myriad MyChoice HRD test as a potential companion diagnostic...
March 16, 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28295194/anti-leukaemic-activity-of-the-tyk2-selective-inhibitor-ndi-031301-in-t-cell-acute-lymphoblastic-leukaemia
#18
Koshi Akahane, Zhaodong Li, Julia Etchin, Alla Berezovskaya, Evisa Gjini, Craig E Masse, Wenyan Miao, Jennifer Rocnik, Rosana Kapeller, Jeremy R Greenwood, Hong Tiv, Takaomi Sanda, David M Weinstock, A Thomas Look
Activation of tyrosine kinase 2 (TYK2) contributes to the aberrant survival of T-cell acute lymphoblastic leukaemia (T-ALL) cells. Here we demonstrate the anti-leukaemic activity of a novel TYK2 inhibitor, NDI-031301. NDI-031301 is a potent and selective inhibitor of TYK2 that induced robust growth inhibition of human T-ALL cell lines. NDI-031301 treatment of human T-ALL cell lines resulted in induction of apoptosis that was not observed with the JAK inhibitors tofacitinib and baricitinib. Further investigation revealed that NDI-031301 treatment uniquely leads to activation of three mitogen-activated protein kinases (MAPKs), resulting in phosphorylation of ERK, SAPK/JNK and p38 MAPK coincident with PARP cleavage...
March 14, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28293393/cytotoxic-and-apoptotic-effects-of-different-extracts-of-artemisia-biennis-willd-on-k562-and-hl-60-cell-lines
#19
Zahra Tayarani-Najaran, Farideh-Sadat Makki, Nafiseh-Sadat Alamolhodaei, Mahdi Mojarrab, Seyed Ahmad Emami
OBJECTIVES: Artemisia is a genus of herbs and small shrubs forms an important part of natural vegetation in Iran. It has been reported that several Artemisia species possess anti-proliferative effects. Considering the value of this genus in anti-cancer researches we have chosen Artemisia biennis for cytotoxic and mechanistic studies. MATERIALS AND METHODS: In this study we have investigated the cytotoxic and apoptotic effects of petroleum ether, dichloromethane, ethyl acetate, ethanol, and ethanol: water (1:1 v/v) extracts of A...
February 2017: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/28292946/nox2-dependent-immunosuppression-in-chronic-myelomonocytic-leukemia
#20
Johan Aurelius, Alexander Hallner, Olle Werlenius, Rebecca Riise, Lars Möllgård, Mats Brune, Markus Hansson, Anna Martner, Fredrik B Thorén, Kristoffer Hellstrand
Chronic myelomonocytic leukemia (CMML) is a myeloproliferative and myelodysplastic neoplasm with few treatment options and dismal prognosis. The role of natural killer (NK) cells and other antileukemic lymphocytes in CMML is largely unknown. We aimed to provide insight into the mechanisms of immune evasion in CMML with a focus on immunosuppressive reactive oxygen species (ROS) formed by the myeloid cell NADPH oxidase-2 (NOX2). The dominant population of primary human CMML cells was found to express membrane-bound NOX2 and to release ROS, which, in turn, triggered extensive PARP-1-dependent cell death in cocultured NK cells, CD8(+) T effector memory cells, and CD8(+) T effector cells...
March 14, 2017: Journal of Leukocyte Biology
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