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https://www.readbyqxmd.com/read/28549786/action-potential-based-mea-platform-for-in-vitro-screening-of-drug-induced-cardiotoxicity-using-human-ipscs-and-rat-neonatal-myocytes
#1
Danny Jans, Geert Callewaert, Olga Krylychkina, Luis Hoffman, Francesco Gullo, Dimiter Prodanov, Dries Braeken
Drug-induced cardiotoxicity poses a negative impact on public health and drug development. Cardiac safety pharmacology issues urged for the preclinical assessment of drug-induced ventricular arrhythmia leading to the design of several in vitro electrophysiological screening assays. In general, patch clamp systems allow for intracellular recordings, while multi-electrode array (MEA) technology detect extracellular activity. Here, we demonstrate a complementary metal oxide semiconductor (CMOS)-based MEA system as a reliable platform for non-invasive, long-term intracellular recording of cardiac action potentials at high resolution...
May 23, 2017: Journal of Pharmacological and Toxicological Methods
https://www.readbyqxmd.com/read/28549569/trpm-channels-as-potential-therapeutic-targets-against-pro-inflammatory-diseases
#2
REVIEW
Susanna Zierler, Sarah Hampe, Wiebke Nadolni
The immune system protects our body against foreign pathogens. However, if it overshoots or turns against itself, pro-inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, or diabetes develop. Ions, the most basic signaling molecules, shape intracellular signaling cascades resulting in immune cell activation and subsequent immune responses. Mutations in ion channels required for calcium signaling result in human immunodeficiencies and highlight those ion channels as valued targets for therapies against pro-inflammatory diseases...
May 3, 2017: Cell Calcium
https://www.readbyqxmd.com/read/28548837/the-role-of-the-hydroxyl-group-in-propofol-protein-target-recognition-insights-from-oniom-studies
#3
Ling Qiu, Jianguo Lin, Qingzhu Liu, Shanshan Wang, Gaochao Lv, Ke Li, Haiming Shi, Zhengkun Huang, Edward J Bertaccini
Propofol (PFL, 1-hydroxyl-2,6-diisopropylbenzene) is currently used widely as one of the most well-known intravenous anesthetics to relieve surgical suffering, but its mechanism of action is not yet clear. Previous experimental studies have demonstrated that the hydroxyl group of PFL plays a dominant role in the molecular recognition of PFL with receptors that lead to hypnosis. To further explore the mechanism of anesthesia induced by PFL in the present work, the exact binding features and interaction details of PFL with three important proteins, human serum albumin (HSA), the pH-gated ion channel from Gloeobacter violaceus (GLIC) and horse spleen apoferritin (HSAF), were investigated systematically by using a rigorous three-layer ONIOM(M06-2X/6-31+G*:PM6:AMBER) method...
May 26, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28547763/new-approaches-towards-the-understanding-of-integral-membrane-proteins-a-structural-perspective-on-g-protein-coupled-receptors
#4
REVIEW
Reinhard Grisshammer
Three-dimensional structure determination of integral membrane proteins has advanced in unprecedented detail our understanding of mechanistic events of how ion channels, transporters, receptors and enzymes function. This exciting progress required a tremendous amount of methods development, as exemplified here with G protein-coupled receptors (GPCRs): Optimizing the production of GPCRs in recombinant hosts; increasing the probability of crystal formation using high-affinity ligands, nanobodies, and minimal G proteins for co-crystallization, thus stabilizing receptors into one conformation; using the T4 lysozyme technology and other fusion partners to promote crystal contacts; advancing crystallization methods including the development of novel detergents, and miniaturization and automation of the lipidic cubic phase crystallization method; the concept of conformational thermostabilization of GPCRs; and developing microfocus X-ray synchrotron technologies to analyze small GPCR crystals...
May 25, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28546905/high-density-microporous-li4ti5o12-microbars-with-superior-rate-performance-for-lithium-ion-batteries
#5
Linkai Tang, Yan-Bing He, Chao Wang, Shuan Wang, Marnix Wagemaker, Baohua Li, Quan-Hong Yang, Feiyu Kang
Nanosized Li4Ti5O12 (LTO) materials enabling high rate performance suffer from a large specific surface area and low tap density lowering the cycle life and practical energy density. Microsized LTO materials have high density which generally compromises their rate capability. Aiming at combining the favorable nano and micro size properties, a facile method to synthesize LTO microbars with micropores created by ammonium bicarbonate (NH4HCO3) as a template is presented. The compact LTO microbars are in situ grown by spinel LTO nanocrystals...
May 2017: Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
https://www.readbyqxmd.com/read/28546857/chloroquine-inhibits-ca-2-permeable-ion-channels-mediated-ca-2-signaling-in-primary-b-lymphocytes
#6
Yi-Fan Wu, Ping Zhao, Xi Luo, Jin-Chao Xu, Lu Xue, Qi Zhou, Mingrui Xiong, Jinhua Shen, Yong-Bo Peng, Meng-Fei Yu, Weiwei Chen, Liqun Ma, Qing-Hua Liu
BACKGROUND: Chloroquine, a bitter tastant, inhibits Ca(2+) signaling, resulting in suppression of B cell activation; however, the inhibitory mechanism remains unclear. RESULTS: In this study, thapsigargin (TG), but not caffeine, induced sustained intracellular Ca(2+) increases in mouse splenic primary B lymphocytes, which were markedly inhibited by chloroquine. Under Ca(2+)-free conditions, TG elicited transient Ca(2+) increases, which additionally elevated upon the restoration of 2 mM Ca(2+)...
2017: Cell & Bioscience
https://www.readbyqxmd.com/read/28546458/proteoglycans-ion-channels-and-cell-matrix-adhesion
#7
REVIEW
Ioli Mitsou, Hinke A B Multhaupt, John R Couchman
Cell surface proteoglycans comprise a transmembrane or membrane-associated core protein to which one or more glycosaminoglycan chains are covalently attached. They are ubiquitous receptors on nearly all animal cell surfaces. In mammals, the cell surface proteoglycans include the six glypicans, CD44, NG2 (CSPG4), neuropilin-1 and four syndecans. A single syndecan is present in invertebrates such as nematodes and insects. Uniquely, syndecans are receptors for many classes of proteins that can bind to the heparan sulphate chains present on syndecan core proteins...
May 25, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28546434/behavioral-deficits-following-withdrawal-from-chronic-ethanol-are-influenced-by-slo-channel-function-in-caenorhabditis-elegans
#8
Luisa L Scott, Scott J Davis, Rachel C Yen, Greg J Ordemann, Sarah K Nordquist, Deepthi Bannai, Jonathan T Pierce
Symptoms of withdrawal from chronic alcohol use are a driving force for relapse in alcohol dependence. Thus, uncovering molecular targets to lessen their severity is key to breaking the cycle of dependence. Using the nematode Caenorhabditis elegans, we tested whether one highly conserved ethanol target, the large-conductance, calcium-activated potassium channel (known as the BK channel or Slo1), modulates ethanol withdrawal. Consistent with a previous report, we found that C. elegans displays withdrawal-related behavioral impairments after cessation of chronic ethanol exposure...
May 25, 2017: Genetics
https://www.readbyqxmd.com/read/28546047/an-impedance-based-approach-using-human-ipsc-derived-cardiomyocytes-significantly-improves-in-vitro-prediction-of-in-vivo-cardiotox-liabilities
#9
Bryan Koci, Gregory Luerman, Anika Duenbostell, Ralf Kettenhofen, Heribert Bohlen, Luke Coyle, Brian Knight, Warren Ku, Walter Volberg, Joseph R Woska, Martha P Brown
Current in vitro approaches to cardiac safety testing typically focus on mechanistic ion channel testing to predict in vivo proarrhythmic potential. Outside of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, structural and functional cardiotoxicity related to chronic dosing effects are of great concern as these effects can impact compound attrition. Development and implementation of an in vitro cardiotoxicity screening platform that effectively identifies these liabilities early in the discovery process should reduce costly attrition and decrease preclinical development time...
May 22, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28545921/a-mechanically-activated-ion-channel-is-functionally-expressed-in-the-mrgprb4-positive-sensory-neurons-which-detect-stroking-of-hairy-skin-in-mice
#10
Soichiro Yamaguchi, Ken-Ichi Otsuguro
Mas-related G-protein coupled receptor B4 (MrgprB4) has been reported to be expressed in the dorsal root ganglion (DRG) neurons which detect stroking of hairy skin of mice. However, the mechanisms by which the MrgprB4 positive (+) neurons respond to adequate stimulus remain unsolved as it was also reported that electrophysiological analysis of cultured MrgprB4+ neurons did not reveal responses to mechanical stimuli. Contrary to the observation, however, in this study we show that the MrgprB4+ neurons functionally express a mechanically activated channel using DRG neurons dissociated from genetically-modified mice whose MrgprB4+ neurons express a red fluorescent protein...
May 22, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28545724/the-role-of-ca-2-in-cell-death-caused-by-oxidative-glutamate-toxicity-and-ferroptosis
#11
REVIEW
Pamela Maher, Klaus van Leyen, Partha Narayan Dey, Birgit Honrath, Amalia Dolga, Axel Methner
Ca(2+) ions play a fundamental role in cell death mediated by oxidative glutamate toxicity or oxytosis, a form of programmed cell death similar and possibly identical to other forms of cell death like ferroptosis. Ca(2+) influx from the extracellular space occurs late in a cascade characterized by depletion of the intracellular antioxidant glutathione, increases in cytosolic reactive oxygen species and mitochondrial dysfunction. Here, we aim to compare oxidative glutamate toxicity with ferroptosis, address the signaling pathways that culminate in Ca(2+) influx and cell death and discuss the proteins that mediate this...
May 12, 2017: Cell Calcium
https://www.readbyqxmd.com/read/28545444/site-specific-his-asp-phosphoproteomic-analysis-of-prokaryotes-reveals-putative-targets-for-drug-resistance
#12
Shu-Jung Lai, I-Fan Tu, Wan-Ling Wu, Jhih-Tian Yang, Louis Y P Luk, Mei-Chin Lai, Yu-Hsuan Tsai, Shih-Hsiung Wu
BACKGROUND: Phosphorylation of amino acid residues on proteins is an important and common post-translational modification in both eukaryotes and prokaryotes. Most research work has been focused on phosphorylation of serine, threonine or tyrosine residues, whereas phosphorylation of other amino acids are significantly less clear due to the controversy on their stability under standard bioanalytical conditions. RESULTS: Here we applied a shotgun strategy to analyze the histidine and aspartate phosphorylations in different microbes...
May 25, 2017: BMC Microbiology
https://www.readbyqxmd.com/read/28544933/cardiotoxic-effect-of-levofloxacin-and-ciprofloxacin-in-rats-with-without-acute-myocardial-infarction-impact-on-cardiac-rhythm-and-cardiac-expression-of-kv4-3-kv1-2-and-nav1-5-channels
#13
Ahmed M Abdelrady, Sawsan A Zaitone, Noha E Farag, Manal S Fawzy, Yasser M Moustafa
Prolongation of QT interval is possible with fluoroquinolones, yet the underlying contributing factors have not been elucidated. Two widely used fluoroquinolone drugs were at the focus of this study in rats with/without acute myocardial dysfunction (AMI) induced by isoproterenol. The effects of levofloxacin and ciprofloxacin on the cardiac mRNA expression of rat Kv4.3, Kv1.2 and Nav1.5 mRNAs were determined. Administration of the two antibiotics produced dose-dependent changes in ECG parameters that were more prominent in rats with AMI than healthy rats; this was accompanied by elevations in serum lactate dehydrogenase and creatine kinase-MB...
May 22, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28544425/free-standing-holey-ni-oh-2-nanosheets-with-enhanced-activity-for-water-oxidation
#14
Xiangkai Kong, Changlin Zhang, Sang Youp Hwang, Qianwang Chen, Zhenmeng Peng
Electrochemical water oxidation is the key technology in water-splitting reactions and rechargeable metal-air batteries, which is very attractive for renewable energy conversion and storage. Replacement of precious catalysts with cost-effective and highly active alternatives is still a great challenge. Herein, based on theoretical predictions, holey structures are designed and fabricated on the free-standing conventional 2D OER catalyst. By well-controlled defects engineering, uniform tiny holes are created on the free-standing Ni(OH)2 nanosheets via a sol-gel method, with the embedded Zn components as the template for holes production...
May 19, 2017: Small
https://www.readbyqxmd.com/read/28544109/express-with-caution-epitope-tags-and-cdna-variants-effects-on-herg-channel-trafficking-half-life-and-function
#15
Marika L Osterbur Badhey, Alexander C Bertalovitz, Thomas V McDonald
INTRODUCTION: Genetic mutations in KCNQ2 which encodes hERG, the alpha subunit of the potassium channel responsible for the IKr current, cause Long QT Syndrome, an inherited cardiac arrhythmia disorder. Electrophysiology techniques are used to correlate genotype with molecular phenotype to determine which mutations identified in patients diagnosed Long QT Syndrome are disease causing, and which are benign. These investigations are usually done using heterologous expression in cell lines, and often, epitope fusion tags are used to enable isolation and identification of the protein of interest...
May 24, 2017: Journal of Cardiovascular Electrophysiology
https://www.readbyqxmd.com/read/28543431/the-effect-of-substrate-stiffness-on-cancer-cell-volume-homeostasis
#16
Meng Wang, Na Chai, Baoyong Sha, Manyun Guo, Jian Zhuang, Feng Xu, Fei Li
Existing studies on the mechanism of cell volume regulation are mainly relevant to ion channels and osmosis in extracellular fluid. Recently, accumulating evidence has shown that cellular mechanical microenvironment also influences the cell volume. Herein, we investigated the regulation of substrate stiffness on the cell volume homeostasis of MCF-7 cells and their following migration behaviors. We found that cell volume increases with increasing substrate stiffness, which could be affected by blocking the cell membrane anion permeability and dopamine receptor...
May 23, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28542706/modulatory-features-of-the-novel-spider-toxin-%C3%AE-trtx-df1a-isolated-from-the-venom-of-the-spider-davus-fasciatus
#17
Fernanda C Cardoso, Zoltan Dekan, Jennifer J Smith, Jennifer R Deuis, Irina Vetter, Volker Herzig, Paul F Alewood, Glenn F King, Richard J Lewis
BACKGROUND AND PURPOSE: Naturally occurring dysfunction in NaV channels results in complex disorders such as chronic pain, making these channels an attractive target for new therapies. In the pursuit of novel NaV modulators, we investigated spider venoms for new inhibitors of NaV channels. EXPERIMENTAL APPROACH: We used high-throughput screens to identify a NaV modulator in venom of the spider Davus fasciatus. Further characterization of this venom peptide was undertaken using fluorescent and electrophysiological assays, molecular modeling and a rodent pain model...
May 24, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28542554/sodium-tanshinone-iia-sulfonate-stimulated-cl-secretion-in-mouse-trachea
#18
Peng-Xiao Chen, Yi-Lin Zhang, Jia-Wen Xu, Ming-Hao Yu, Jie-Hong Huang, Lei Zhao, Wen-Liang Zhou
Sodium tanshinone IIA sulfonate (STS) is a derivate of tanshinone IIA, a lipophilic compound in Salvia miltiorrhiza. This study aimed to investigate the effect of STS on ion transport in mouse tracheal epithelium and the mechanisms underlying it. Short-circuit current (Isc) was measured to evaluate the effect of STS on transepithelial ion transport. Intracellular Ca2+ imaging was performed to observe intracellular Ca2+ concentration ([Ca2+]i) changes induced by STS in primary cultured mouse tracheal epithelial cells...
2017: PloS One
https://www.readbyqxmd.com/read/28542428/age-dependent-electrical-and-morphological-remodeling-of-the-drosophila-heart-caused-by-herg-seizure-mutations
#19
Karen Ocorr, Alexander Zambon, Yoav Nudell, Santiago Pineda, Soda Diop, Min Tang, Takeshi Akasaka, Erika Taylor
Understanding the cellular-molecular substrates of heart disease is key to the development of cardiac specific therapies and to the prevention of off-target effects by non-cardiac targeted drugs. One of the primary targets for therapeutic intervention has been the human ether a go-go (hERG) K+ channel that, together with the KCNQ channel, controls the rate and efficiency of repolarization in human myocardial cells. Neither of these channels plays a major role in adult mouse heart function; however, we show here that the hERG homolog seizure (sei), along with KCNQ, both contribute significantly to adult heart function as they do in humans...
May 19, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28541651/channel-crack-designed-gold-pu-sponge-for-highly-elastic-piezoresistive-sensor-with-excellent-detectability
#20
Yun-Hui Wu, Hai-Zhou Liu, Song Chen, Xuchu Dong, Ping-Ping Wang, Shuqi Liu, Yong Lin, Yong Wei, Lan Liu
It is a great challenge to fabricate piezoresistive sensors that possess high elasticity, large-area compliance and excellent detectability to satisfy both extremely tiny and large human activities monitoring. Herein, a novel and facile strategy is reported to manufacture highly elastic channel crack-based gold@PU sponge piezoresistive material. The elastic 3D conductive network is successfully prepared by gold ion sputtering, and channel cracks are skillfully designed on the 3D sponge skeletons. Such novel structure makes these fabricated sensors are capable of monitoring both tiny and large human motions, which originate from the nano-crack joint sensing mechanism and physical contact of conductive interconnected network...
May 25, 2017: ACS Applied Materials & Interfaces
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