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https://www.readbyqxmd.com/read/29053969/pebp1-wardens-ferroptosis-by-enabling-lipoxygenase-generation-of-lipid-death-signals
#1
Sally E Wenzel, Yulia Y Tyurina, Jinming Zhao, Claudette M St Croix, Haider H Dar, Gaowei Mao, Vladimir A Tyurin, Tamil S Anthonymuthu, Alexandr A Kapralov, Andrew A Amoscato, Karolina Mikulska-Ruminska, Indira H Shrivastava, Elizabeth M Kenny, Qin Yang, Joel C Rosenbaum, Louis J Sparvero, David R Emlet, Xiaoyan Wen, Yoshinori Minami, Feng Qu, Simon C Watkins, Theodore R Holman, Andrew P VanDemark, John A Kellum, Ivet Bahar, Hülya Bayır, Valerian E Kagan
Ferroptosis is a form of programmed cell death that is pathogenic to several acute and chronic diseases and executed via oxygenation of polyunsaturated phosphatidylethanolamines (PE) by 15-lipoxygenases (15-LO) that normally use free polyunsaturated fatty acids as substrates. Mechanisms of the altered 15-LO substrate specificity are enigmatic. We sought a common ferroptosis regulator for 15LO. We discovered that PEBP1, a scaffold protein inhibitor of protein kinase cascades, complexes with two 15LO isoforms, 15LO1 and 15LO2, and changes their substrate competence to generate hydroperoxy-PE...
October 19, 2017: Cell
https://www.readbyqxmd.com/read/29053865/beta-burst-dynamics-in-parkinson-s-disease-off-and-on-dopaminergic-medication
#2
Gerd Tinkhauser, Alek Pogosyan, Huiling Tan, Damian M Herz, Andrea A Kühn, Peter Brown
Exaggerated basal ganglia beta activity (13-35 Hz) is commonly found in patients with Parkinson's disease and can be suppressed by dopaminergic medication, with the degree of suppression being correlated with the improvement in motor symptoms. Importantly, beta activity is not continuously elevated, but fluctuates to give beta bursts. The percentage number of longer beta bursts in a given interval is positively correlated with clinical impairment in Parkinson's disease patients. Here we determine whether the characteristics of beta bursts are dependent on dopaminergic state...
October 10, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/29053764/contribution-of-calpain-and-caspases-to-cell-death-in-cultured-monkey-rpe-cells
#3
Emi Nakajima, Katherine B Hammond, Masayuki Hirata, Thomas R Shearer, Mitsuyoshi Azuma
Purpose: AMD is the leading cause of human vision loss after 65 years of age. Several mechanisms have been proposed: (1) age-related failure of the choroidal vasculature leads to loss of RPE; (2) RPE dysfunctions due to accumulation of phagocytized, but unreleased A2E (N-retinylidene-N-retinylethanolamine); (3) zinc deficiency activation of calpain and caspase proteases, leading to cell death. The purpose of the present study is to compare activation of calpain and caspase in monkey RPE cells cultured under hypoxia or with A2E...
October 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/29053735/characterization-of-the-first-knock-out-aldh7a1-zebrafish-model-for-pyridoxine-dependent-epilepsy-using-crispr-cas9-technology
#4
Nikita Zabinyakov, Garrett Bullivant, Feng Cao, Matilde Fernandez Ojeda, Zheng Ping Jia, Xiao-Yan Wen, James J Dowling, Gajja S Salomons, Saadet Mercimek-Andrews
Pyridoxine dependent epilepsy (PDE) is caused by likely pathogenic variants in ALDH7A1 (PDE-ALDH7A1) and inherited autosomal recessively. Neurotoxic alpha-amino adipic semialdehyde (alpha-AASA), piperideine 6-carboxylate and pipecolic acid accumulate in body fluids. Neonatal or infantile onset seizures refractory to anti-epileptic medications are clinical features. Treatment with pyridoxine, arginine and lysine-restricted diet does not normalize neurodevelopmental outcome or accumulation of neurotoxic metabolites...
2017: PloS One
https://www.readbyqxmd.com/read/29053584/lomefloxacin-induces-oxidative-stress-and-apoptosis-in-colo829-melanoma-cells
#5
Artur Beberok, Dorota Wrześniok, Martyna Szlachta, Jakub Rok, Zuzanna Rzepka, Michalina Respondek, Ewa Buszman
Although some fluoroquinolones have been found to exert anti-tumor activity, studies on the effect of these drugs on melanoma cells are relatively rare. The aim of this study was to examine the effect of lomefloxacin on cell viability, reactive oxygen species production, redox balance, cell cycle distribution, DNA fragmentation, and apoptosis in COLO829 melanoma cells. Lomefloxacin decreases the cell viability in a dose- and time-dependent manner. For COLO829 cells treated with the drug for 24, 48, and 72 h, the values of IC50 were found to be 0...
October 20, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29053567/eco-friendly-formulated-zinc-oxide-nanoparticles-induction-of-cell-cycle-arrest-and-apoptosis-in-the-mcf-7-cancer-cell-line
#6
Amin Boroumand Moghaddam, Mona Moniri, Susan Azizi, Raha Abdul Rahim, Arbakariya Bin Ariff, Mohammad Navaderi, Rosfarizan Mohamad
Green products have strong potential in the discovery and development of unique drugs. Zinc oxide nanoparticles (ZnO NPs) have been observed to have powerful cytotoxicity against cells that cause breast cancer. The present study aims to examine the cell cycle profile, status of cell death, and pathways of apoptosis in breast cancer cells (MCF-7) treated with biosynthesized ZnO NPs. The anti-proliferative activity of ZnO NPs was determined using MTT assay. Cell cycle analysis and the mode of cell death were evaluated using a flow cytometry instrument...
October 20, 2017: Genes
https://www.readbyqxmd.com/read/29053381/adaptive-networkprofiler-for-identifying-cancer-characteristic-specific-gene-regulatory-networks
#7
Heewon Park, Teppei Shimamura, Seiya Imoto, Satoru Miyano
There is currently much discussion about sample (patient)-specific gene regulatory network identification, since the efficiently constructed sample-specific gene networks lead to effective personalized cancer therapy. Although statistical approaches have been proposed for inferring gene regulatory networks, the methods cannot reveal sample-specific characteristics because the existing methods, such as an L1-type regularization, provide averaged results for all samples. Thus, we cannot reveal sample-specific characteristics in transcriptional regulatory networks...
October 20, 2017: Journal of Computational Biology: a Journal of Computational Molecular Cell Biology
https://www.readbyqxmd.com/read/29053257/orthogonal-screening-of-anti-cancer-drugs-using-an-open-access-microfluidic-tissue-array-system
#8
Dongguo Lin, Peiwen Li, Jinqiong Lin, Bowen Shu, Weixin Wang, Qiong Zhang, Na Yang, Dayu Liu, Banglao Xu
Screening for potential drug combinations presents significant challenges to the current microfluidic cell culture systems, due to the requirement of flexibility in liquid handling. To overcome this limitation, we present here an open-access microfluidic tissue array system specifically designed for drug combination screening. The microfluidic chip features a key structure in which a nanoporous membrane is sandwiched by a cell culture chamber array layer and a corresponded media reservoir array layer. The microfluidic approach takes advantage of the characteristics of the nanoporous membrane: on one side, this membrane permits the flow of air but not liquid, thus acting as a flow-stop valve to enable automatic cell distribution; on the other side, it allows diffusion-based media exchange and thus, mimics the endothelial layer...
October 20, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/29053217/behavioral-control-by-striatal-a2a-dopamine-d2-receptor-heteromers
#9
Jaume Taura, Marta Valle-León, Kristoffer Sahlholm, Masahiko Watanabe, Katheleen Van Craenenbroeck, Víctor Fernández-Dueñas, Sergi Ferré, Francisco Ciruela
G protein-coupled receptors (GPCR) exhibit the ability to form receptor complexes that include molecularly different GPCR (i.e. GPCR heteromers), which endow them with singular functional and pharmacological characteristics. The relative expression of GPCR heteromers remains a matter of intense debate. Recent studies support that adenosine A2A receptors (A2A R) and dopamine D2 receptors (D2 R) predominantly form A2A R-D2 R heteromers in the striatum. The aim of the present study was evaluating the behavioral effects of pharmacological manipulation and genetic blockade of A2A R and D2 R within the frame of such a predominant striatal heteromeric population...
October 20, 2017: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/29053119/-peptidergic-nootropic-therapy-in-cerebral-palsy-associated-with-epilepsy
#10
A A Kholin, N N Zavadenko, E S Il Ina, L M Kolpakchi, I D Fedonyuk, R C Bembeeva, E S Esipova
AIM: To assess the efficacy and safety of сortexin in the treatment of children with cerebral palsy (CP) combined with epilepsy. MATERIAL AND METHODS: Eighty-four patients (55 boys and 29 girls), aged from 1 to 11 years, with CP combined with epilepsy received cortexin together with antiepileptic drugs (AEDs). Cortexin was administered in doses of 5-10 mg depending on the patient's age and body weight intramuscularly during hospitalization. RESULTS AND CONCLUSION: Cortexin as add-on to AEDs reduced for more than two times the number of seizures, along with improvement of motor function, in 31 (36...
2017: Zhurnal Nevrologii i Psikhiatrii Imeni S.S. Korsakova
https://www.readbyqxmd.com/read/29052375/-referencing-and-inosculating-discussion-on-modern-research-strategy-for-ethnomedicines
#11
Zhi-Yong Li, Xing-Yun Chai, Tao Yuan, Guang-Zhi Ding, Hai-Ying Tong
This article reviewed the current situation of ethnomedicines in China, and propos that the important research on ethnomedicine is to focus on the theoretical and empirical characteristics of ethnomedicine and the special features in the processes of collecting,processing and clinical application of ethnomedicine, which will be benefit to find the research principles and methods with the characteristics of ethnomedicine. These principles include making clear of the effective substances and mechanisms, and theoretical and empirical characteristics of ethnomedicine...
April 2017: Zhongguo Zhong Yao za Zhi, Zhongguo Zhongyao Zazhi, China Journal of Chinese Materia Medica
https://www.readbyqxmd.com/read/29051554/recombinant-incretin-secreting-microbe-improves-metabolic-dysfunction-in-high-fat-diet-fed-rodents
#12
Paul M Ryan, Elaine Patterson, Robert M Kent, Helena Stack, Paula M O'Connor, Kiera Murphy, Veronica L Peterson, Rupasri Mandal, David S Wishart, Timothy G Dinan, John F Cryan, Randy J Seeley, Catherine Stanton, R Paul Ross
The gut hormone glucagon-like peptide (GLP)-1 and its analogues represent a new generation of anti-diabetic drugs, which have also demonstrated propensity to modulate host lipid metabolism. Despite this, drugs of this nature are currently limited to intramuscular administration routes due to intestinal degradation. The aim of this study was to design a recombinant microbial delivery vector for a GLP-1 analogue and assess the efficacy of the therapeutic in improving host glucose, lipid and cholesterol metabolism in diet induced obese rodents...
October 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29051480/nox4-functions-as-a-mitochondrial-energetic-sensor-coupling-cancer-metabolic-reprogramming-to-drug-resistance
#13
Karthigayan Shanmugasundaram, Bijaya K Nayak, William E Friedrichs, Dharam Kaushik, Ronald Rodriguez, Karen Block
The molecular mechanisms that couple glycolysis to cancer drug resistance remain unclear. Here we identify an ATP-binding motif within the NADPH oxidase isoform, NOX4, and show that ATP directly binds and negatively regulates NOX4 activity. We find that NOX4 localizes to the inner mitochondria membrane and that subcellular redistribution of ATP levels from the mitochondria act as an allosteric switch to activate NOX4. We provide evidence that NOX4-derived reactive oxygen species (ROS) inhibits P300/CBP-associated factor (PCAF)-dependent acetylation and lysosomal degradation of the pyruvate kinase-M2 isoform (PKM2)...
October 19, 2017: Nature Communications
https://www.readbyqxmd.com/read/29051447/revelation-of-different-nanoparticle-uptake-behavior-in-two-standard-cell-lines-nih-3t3-and-a549-by-flow-cytometry-and-time-lapse-imaging
#14
André Jochums, Elsa Friehs, Franziska Sambale, Antonina Lavrentieva, Detlef Bahnemann, Thomas Scheper
The uptake of nanomaterials into different cell types is a central pharmacological issue for the determination of nanotoxicity as well as for the development of drug delivery strategies. Most responses of the cells depend on their intracellular interactions with nanoparticles (NPs). Uptake behavior can be precisely investigated in vitro, with sensitive high throughput methods such as flow cytometry. In this study, we investigated two different standard cell lines, human lung carcinoma (A549) and mouse fibroblast (NIH/3T3) cells, regarding their uptake behavior of titanium dioxide NPs...
July 19, 2017: Toxics
https://www.readbyqxmd.com/read/29051318/evaluation-of-the-selectivity-and-cysteine-dependence-of-inhibitors-across-the-regulator-of-g-protein-signaling-family
#15
Michael P Hayes, Christopher R Bodle, David L Roman
Since their discovery over 20 years ago, Regulators of G Protein Signaling (RGS) proteins have received considerable attention as potential drug targets due to their ability to modulate G α activity. Efforts to identify small molecules capable of inhibiting the protein-protein interaction between activated G α subunits and RGS proteins have yielded a substantial number of inhibitors, especially towards the well-studied RGS4. These efforts also identified that many of these small molecules inhibit the protein- protein interaction through covalent modification of Cysteine residues within the RGS domain that are located distal to the G α -binding interface...
October 19, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/29051147/organic-anion-transporting-polypeptides-oatps-mediated-drug-drug-interaction-study-between-rosuvastatin-and-cyclosporine-a-in-chimeric-mice-with-humanized-liver
#16
Masashi Uchida, Yoriko Tajima, Masakazu Kakuni, Yutaka Kageyama, Taro Okada, Eri Sakudara, Chise Tateno, Ryoji Hayashi
The influence of transporters on the pharmacokinetics of drugs is being increasingly recognized, and DDIs via transporters may be a risk factor for adverse events. Cyclosporine A, a strong OATP-inhibitor, has been reported to increase the systemic exposure of rosuvastatin, an OATP-substrate, by 7.1-fold in clinical studies. PXB-mice are chimeric mice with humanized livers that are highly repopulated with human hepatocytes, and have been widely used for drug discovery in DMPK studies. In the present study, we examined in vivo and in vitro DDIs between rosuvastatin and cyclosporine A in PXB-mice and fresh human hepatocytes (PXB-cells) obtained from PXB-mice...
October 19, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29051063/defining-optimal-permeant-characteristics-for-ultrasound-mediated-gastrointestinal-delivery
#17
Carl M Schoellhammer, Yiyun Chen, Cody Cleveland, Daniel Minahan, Taylor Bensel, June Y Park, Sarah Saxton, Young-Ah Lucy Lee, Lucas Booth, Robert Lange, Giovanni Traverso
Ultrasound-mediated drug delivery in the gastrointestinal (GI) tract is a bourgeoning area of study. Localized, low-frequency ultrasound has recently been shown to enable significant enhancement in delivery of a broad set of active pharmaceutical ingredients including small molecules, proteins, and nucleic acids without any formulation or encapsulation of the therapeutic. Traditional chemical formulations are typically required to protect, stabilize, and enable the successful delivery of a given therapeutic...
October 16, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29051021/anti-pdgfra-antibodies-predict-for-response-to-nilotinib-in-steroid-refractory-dependent-cgvhd
#18
George L Chen, Paul A Carpenter, Raewyn Broady, Tara K Gregory, Laura J Johnston, Barry E Storer, Jan H Beumer, Jingxin Qiu, Kiara Cerda, Ryan Le, Joanne M Otani, Hong Liu, Maureen A Ross, Sally Arai, Mary E D Flowers, Philip L McCarthy, David B Miklos
Imatinib has clinical activity in chronic graft-versus-host disease (cGvHD), a significant complication of allogeneic hematopoietic cell transplant. Nilotinib is a tyrosine kinase inhibitor that targets the same receptors as imatinib but with different affinities. We tested the hypothesis that nilotinib is safe and has clinical activity in cGvHD. 33 participants were enrolled in a phase 1/2 dose escalation and dose extension clinical trial of nilotinib for the treatment of steroid refractory or dependent cGvHD (ClinicalTrials...
October 16, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29050968/discovery-and-electrophysiological-characterization-of-skf-32802-a-novel-herg-agonist-found-through-a-large-scale-structural-similarity-search
#19
Brian T Donovan, Deepak Bandyopadhyay, Chaya Duraiswami, Christopher J Nixon, Claire Y Townsend, Stan F Martens
Despite the importance of the hERG channel in drug discovery and the sizable number of antagonist molecules discovered, only a few hERG agonists have been discovered. Here we report a novel hERG agonist; SKF-32802 and a structural analog of the agonist NS3623, SB-335573. These were discovered through a similarity search of published hERG agonists. SKF-32802 incorporates an amide linker rather than NS3623's urea, resulting in a compound with a different mechanism of action. We find that both compounds decrease the time constant of open channel kinetics, increase the amplitude of the envelope of tails assay, mildly increased the amplitude of the IV curve, bind the hERG channel in either open or closed states, increase the plateau of the voltage dependence of activation and modulate the effects of the hERG antagonist, quinidine...
October 16, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/29050945/aptamers-as-therapeutic-middle-molecules
#20
REVIEW
Yoshikazu Nakamura
Therapeutic molecules can be classified as low-, middle- and high-molecular weight drugs depending on their molecular masses. Antibodies represent high-molecular weight drugs and their clinical applications have been developing rapidly. Aptamers, on the other hand, are middle-molecular weight molecules that are short, single-stranded nucleic acid sequences that are selected in vitro from large oligonucleotide libraries based on their high affinity to a target molecule. Hence, aptamers can be thought of as a nucleic acid analog to antibodies...
October 16, 2017: Biochimie
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