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https://www.readbyqxmd.com/read/29342154/three-unrelated-and-unexpected-amino-acids-determine-the-susceptibility-of-the-interface-cysteine-to-a-sulfhydryl-reagent-in-the-triosephosphate-isomerases-of-two-trypanosomes
#1
Selma Díaz-Mazariegos, Nallely Cabrera, Ruy Perez-Montfort
Proteins with great sequence similarity usually have similar structure, function and other physicochemical properties. But in many cases, one or more of the physicochemical or functional characteristics differ, sometimes very considerably, among these homologous proteins. To better understand how critical amino acids determine quantitative properties of function in proteins, the responsible residues must be located and identified. This can be difficult to achieve, particularly in cases where multiple amino acids are involved...
2018: PloS One
https://www.readbyqxmd.com/read/29341608/molecular-dynamics-pinpoint-the-global-fluorine-effect-in-balanoids-binding-to-pkc%C3%AE%C2%B5-and-pka
#2
Ari Hardianto, Fei Liu, Shoba Ranganathan
(-)-Balanol is an ATP mimic that inhibits protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA) with little selectivity. While PKA is known as a tumour promoter, PKC isozymes can be tumour promoters or suppressors. In particular, PKCε is frequently involved in tumorigenesis and a potential target for anticancer drugs. We recently reported that stereospecific fluorination of balanol yielded a balanoid with enhanced selectivity for PKCε over other PKC isozymes and PKA, although the global fluorine effect behind the selectivity enhancement is not fully understood...
January 17, 2018: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29341465/p2y12-deficiency-in-mouse-impairs-noradrenergic-system-in-brain-and-alters-anxiety-like-neurobehavior-and-memory
#3
Fang Zheng, Qiang Zhou, Yin Cao, Hailian Shi, Hui Wu, Beibei Zhang, Fei Huang, Xiaojun Wu
Purinergic receptor P2Y12 (P2Y12 ), a G protein-coupled (GPCR) purinergic receptor, is widely distributed in nervous system and involved in the progression of neurological diseases such as multiple sclerosis and neuropathic pain. The central noradrenergic system actively participates in a number of neurophysiological processes. Nevertheless, whether there is any direct relevance between P2Y12 and noradrenergic signal transduction remains unknown. In the present study, we tested the hypothesis that lack of P2Y12 impaired noradrenergic signal transduction in mouse brain...
January 17, 2018: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/29341352/misregulation-of-membrane-trafficking-processes-in-human-nonalcoholic-steatohepatitis
#4
Anika L Dzierlenga, Nathan J Cherrington
Nonalcoholic steatohepatitis (NASH) remodels the expression and function of genes and proteins that are critical for drug disposition. This study sought to determine whether disruption of membrane protein trafficking pathways in human NASH contributes to altered localization of multidrug resistance-associated protein 2 (MRP2). A comprehensive immunoblot analysis assessed the phosphorylation, membrane translocation, and expression of transporter membrane insertion regulators, including several protein kinases (PK), radixin, MARCKS, and Rab11...
January 17, 2018: Journal of Biochemical and Molecular Toxicology
https://www.readbyqxmd.com/read/29340712/membrane-position-dependency-of-the-pka-and-conductivity-of-the-protein-ion-channel
#5
Nikolay A Simakov, Maria G Kurnikova
The dependency of current-voltage characteristics of the α-hemolysin channel on the channel position within the membrane was studied using Poisson-Nernst-Planck theory of ion conductivity with soft repulsion between mobile ions and protein atoms (SP-PNP). The presence of the membrane environment also influences the protonation state of the residues at the boundary of the water-lipid interface. In this work, we predict that Asp and Lys residues at the protein rim change their protonation state upon penetration to the lipid environment...
January 16, 2018: Journal of Membrane Biology
https://www.readbyqxmd.com/read/29339522/effect-of-beta-agonists-on-lam-progression-and-treatment
#6
Kang Le, Wendy K Steagall, Mario Stylianou, Gustavo Pacheco-Rodriguez, Thomas N Darling, Martha Vaughan, Joel Moss
Lymphangioleiomyomatosis (LAM), a rare disease of women, is associated with cystic lung destruction resulting from the proliferation of abnormal smooth muscle-like LAM cells with mutations in the tuberous sclerosis complex (TSC) genes TSC1 and/or TSC2 The mutant genes and encoded proteins are responsible for activation of the mechanistic target of rapamycin (mTOR), which is inhibited by sirolimus (rapamycin), a drug used to treat LAM. Patients who have LAM may also be treated with bronchodilators for asthma-like symptoms due to LAM...
January 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29338209/injectable-self-healing-zwitterionic-hydrogels-based-on-dynamic-benzoxaborole-sugar-interactions-with-tunable-mechanical-properties
#7
Yangjun Chen, Wenda Wang, Di Wu, Masanori Nagao, Dennis G Hall, Thomas Thundat, Ravin Narain
Dynamic hydrogels based on arylboronic esters have been considered as ideal platforms for biomedical applications given their self-healing and injectable characteristics. However, there still exist some critical issues that need to be addressed or improved, including hydrogel biocompatibility, physiological usability, and tunability of mechanical properties. Here, two kinds of phospholipid bioinspired MPC copolymers, one is zwitterionic copolymer (PMB) containing a fixed 15 mol% of benzoxaborole (pKa ≈ 7...
January 16, 2018: Biomacromolecules
https://www.readbyqxmd.com/read/29337365/loss-of-sti1-mediated-neuronal-survival-and-differentiation-in-disease-associated-mutations-of-prion-protein
#8
M C Landemberger, G P Oliveira, C F Machado, K J Gollob, V R Martins
Cellular prion protein (PrPC ) is widely expressed and displays a variety of well-described functions in the central nervous system (CNS). Mutations of the PRNP gene are known to promote genetic human spongiform encephalopathies, but the components of gain- or loss-of-function mutations to PrPC remain a matter for debate. Among the proteins described to interact with PrPC is stress inducible protein 1 (STI1), a co-chaperonin that is secreted from astrocytes and triggers neuroprotection and neuritogenesis through its interaction with PrPC ...
January 16, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29336553/catalytic-mechanism-of-cruzain-from-trypanosoma-cruzi-as-determined-from-solvent-kinetic-isotope-effects-of-steady-state-and-pre-steady-state-kinetics
#9
Xiang Zhai, Thomas D Meek
Cruzain, an important drug target for Chagas disease, is a member of Clan CA of the cysteine proteases. Understanding the catalytic mechanism of cruzain is vital to the design of new inhibitors. To this end, we have performed pH-rate profiles for substrates and affinity agents, and have determined solvent kinetic isotope effects in pre-steady-state and steady-state modes using three substrates: Cbz-Phe-Arg-AMC, Cbz-Arg-Arg-AMC and Cbz-Arg-Ala-AMC. The pH-rate profile of kcat/Km for Cbz-Arg-Arg-AMC indicated groups of pK1 = 6...
January 16, 2018: Biochemistry
https://www.readbyqxmd.com/read/29336505/signalling-transduction-events-involved-in-agonist-induced-pge2-ep4-receptor-externalization-in-cultured-rat-dorsal-root-ganglion-neurons
#10
W Ma, B St-Jacques
BACKGROUND: Prostaglandin E2 (PGE2) enriched in inflamed tissues contributes to chronic pain by sensitizing nociceptive dorsal root ganglion (DRG) neurons (nociceptors). Of four PGE2 receptors (EP1-4), EP4 plays a major role in PGE2-induced nociceptor sensitization. We have previously reported that PGE2 or EP4 agonists stimulated EP4 externalization in cultured DRG neurons and this event contributes to nociceptor sensitization. However, the signalling transduction events governing this event remain unknown...
January 16, 2018: European Journal of Pain: EJP
https://www.readbyqxmd.com/read/29335871/validation-of-tautomeric-and-protomeric-binding-modes-by-free-energy-calculations-a-case-study-for-the-structure-based-optimization-of-d-amino-acid-oxidase-inhibitors
#11
Zoltán Orgován, György G Ferenczy, Thomas Steinbrecher, Bence Szilágyi, Dávid Bajusz, György M Keserű
Optimization of fragment size D-amino acid oxidase (DAAO) inhibitors was investigated using a combination of computational and experimental methods. Retrospective free energy perturbation (FEP) calculations were performed for benzo[d]isoxazole derivatives, a series of known inhibitors with two potential binding modes derived from X-ray structures of other DAAO inhibitors. The good agreement between experimental and computed binding free energies in only one of the hypothesized binding modes strongly support this bioactive conformation...
January 15, 2018: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/29334461/enhanced-proton-loss-from-neutral-free-radicals-towards-carbon-centered-superacids
#12
John C Walton
Radical centers close to protons are known to enhance their dissociation. Investigation of the generality of this Radical Enhanced Deprotonation (RED-shift) phenomenon and the kinds of structures in which it operates are reported. The pKas for sulfinic, sulfonic, pentan-2,4-dione and Meldrum's acid species, with adjacent radicals centered on C-, N- and O-atoms, were computed by a DFT method from free energies of deprotonation. All series showed significant RED-shifts that increased with the electronegativity of the radical center...
January 15, 2018: Journal of Physical Chemistry. A
https://www.readbyqxmd.com/read/29333858/mineral-and-base-catalyzed-hydrolysis-of-organophosphate-flame-retardants-a-potential-major-fate-controlling-sink-in-soil-and-aquatic-environments
#13
Yida Fang, Erin Kim, Timothy J Strathmann
The ubiquitous occurrence of organophosphate flame retardants (OPFRs) in aquatic and soil environments poses significant risks to human health and ecosystems. Here, we report on the hydrolysis of six OPFRs and three structural analogues in the absence and presence of metal (hydr)oxide minerals. Eight of the target compounds showed marked degradation in alkaline solutions (pH 9-12) with half-lives ranging from 0.02 - 170 d. Kinetics follow a second-order rate law with apparent rate constants for base-catalyzed hydrolysis (kB) ranging from 0...
January 15, 2018: Environmental Science & Technology
https://www.readbyqxmd.com/read/29333720/degree-of-sglt1-phosphorylation-is-associated-with-but-does-not-determine-segment-specific-glucose-transport-features-in-the-porcine-small-intestines
#14
Stefanie Klinger, Patrick Lange, Elisabeth Brandt, Karin Hustedt, Bernd Schröder, Gerhard Breves, Jens Herrmann
Glucose-induced electrogenic ion transport is higher in the porcine ileum compared with the jejunum despite equal apical abundance of SGLT1. The objective of this study was a detailed determination of SGLT1 and GLUT2 expressions at mRNA and protein levels along the porcine small intestinal axis. Phosphorylation of SGLT1 at serine 418 was assessed as a potential modulator of activity. Porcine intestinal tissues taken along the intestinal axis 1 h or 3 h after feeding were analyzed for relative mRNA (RT-PCR) and protein levels (immunoblot) of SGLT1, pSGLT1, GLUT2, (p)AMPK, β2 -receptor, and PKA substrates...
January 2018: Physiological Reports
https://www.readbyqxmd.com/read/29332800/acidity-of-substituted-cathinones-studied-by-capillary-electrophoresis-using-the-standard-and-fast-alternative-approaches
#15
Michał Woźniakiewicz, Paweł Mateusz Nowak, Małgorzata Gołąb, Piotr Adamowicz, Maria Kała, Paweł Kościelniak
Cathinone derivatives are notorious but still weakly characterized molecules, known mainly as components of the designer and illicit drugs. The knowledge on their acidity is scarce and incomplete, therefore, we decided to determine the pKa values for six of them: 2-methylmethcathinone, 3-methylmethcathinone, 4-methylmethcathinone, α-pyrrolidinovalerophenone, methylenedioxypyrovalerone and ephedrone. For that purpose we employed capillary electrophoresis, which is known for its accurateness in comparison to other analytical techniques...
April 1, 2018: Talanta
https://www.readbyqxmd.com/read/29332488/role-of-the-hippocampal-5-ht1a-receptor-mediated-camp-pka-signalling-pathway-in-sevoflurane-induced-cognitivedysfunction-in-aged-rats
#16
Yi Qiu, Ying Wang, Xiaodong Wang, Caixia Wang, Zhong-Yuan Xia
Objective This study aimed to evaluate the role of the hippocampal 5-hydroxytryptamine-1A (5-HT1A)-mediated cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signalling pathway in sevoflurane-induced cognitive dysfunction in aged rats. Methods Sixty 18-month-old Sprague-Dawley rats were divided into the control (n = 30) and experimental (Sev, n = 30) groups. The experimental group inhaled 50% air/oxygen mixture (2 L/min) and 2% sevoflurane for 4 hours. The control group inhaled 50% air/oxygen mixture (2 L/min) for 4 hours...
January 1, 2018: Journal of International Medical Research
https://www.readbyqxmd.com/read/29332400/multiscale-kinetic-modeling-reveals-ensemble-of-cl-h-exchange-pathways-in-clc-ec1-antiporter
#17
Heather B Mayes, Sangyun Lee, Andrew D White, Gregory A Voth, Jessica M J Swanson
Despite several years of research, the ion exchange mechanisms in chloride/proton antiporters and many other coupled transporters are not yet understood at the molecular level. Here, we present a novel approach to kinetic modeling and apply it to ion exchange in ClC-ec1. Our multiscale kinetic model (MKM) is developed by 1) calculating the state-to-state rate coefficients with reactive and polarizable molecular dynamics simulations, 2) optimizing these rates in a global kinetic network, and 3) predicting new electrophysiological results...
January 14, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29331607/solid-dispersions-to-enhance-the-delivery-of-a-potential-drug-candidate-lpsf-fz4-for-the-treatment-of-schistosomiasis
#18
Giovanna C R M Schver, Dajun D Sun, Salvana P M Costa, Keyla E R Silva, Jamerson F Oliveira, Larissa Araujo Rolim, Mônica Camelo Pessôa de Azevedo Albuquerque, André de Lima Aires, Maria do Carmo A Lima, Ivan R Pitta, Ping I Lee, Pedro J Rolim-Neto
Drug candidate LPSF/FZ4 with promising schistosomicidal properties in vitro was previously synthesized. However, LPSF/FZ4 has limited aqueous solubility (<1 μg/mL), leading to ineffective dissolution and, therefore, no meaningful in vivo comparative studies could be pursued. This study was aimed to develop a proper amorphous solid dispersion (SD) to enhance the solubility and dissolution rate of LPSF/FZ4 such that its biological activity could be investigated. To better understand its physiological behavior, the pKa of LPSF/FZ4, a monoprotic weak acid with NH group at the imidazolidine ring, was first determined to be 8...
January 10, 2018: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29331388/e4bp4-inhibits-angii-induced-apoptosis-in-h9c2-cardiomyoblasts-by-activating-the-pi3k-akt-pathway-and-promoting-calcium-uptake
#19
Bih-Cheng Chen, Marthandam Asokan Shibu, Chia-Hua Kuo, Chia-Yao Shen, Shu Nu Chang-Lee, Chao-Hung Lai, Ray-Jade Chen, Chun-Hsu Yao, Vijaya Padma Viswanadha, Jian-Shen Liu, Wei-Kung Chen, Chih-Yang Huang
The bZIP transcription factor E4BP4 is a survival factor that is known to be elevated in diseased heart and promote cell survival. In this study the role of E4BP4 on angiotensin-II (AngII)-induced apoptosis has been examined in in vitro cell model. H9c2 cardiomyoblast cells that overexpressed E4BP4 were exposed to AngII to observe the cardio-protective effects of E4BP4 on hypertension related apoptosis. The results from TUNEL assays revealed that E4BP4 significantly attenuated AngII-induced apoptosis. Further analysis by Western blot and RT-PCR showed that E4BP4 inhibited AngII-induced IGF-II mRNA expression and cleavage of caspase-3 through the PI3K-Akt pathway...
January 10, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29330129/estradiol-up-regulates-l-type-ca2-channels-via-membrane-bound-estrogen-receptor-phosphoinositide-3kinase-akt-camp-response-element-binding-protein-signaling-pathway
#20
Xiaoyan Yang, Xiaofang Mao, Gao Xu, Shasha Xing, Ansuman Chattopadhyay, Si Jin, Guy Salama
BACKGROUND: In long QT type-2 (LQT2), women are more prone to lethal arrhythmias called Torsade de Pointes (TdP) than men. We previously reported that 17-β-estradiol (E2) upregulates L-type Ca2+-channels and current (ICa,L) (∼30%) in rabbit ventricular myocytes by a classical genomic-mechanism mediated by estrogen-receptor-α (ER)α. In LQT2 ( IKr-blockade or bradycardia), the higher Ca2+ influx via ICa,L, causes Ca2+-overload, spontaneous sarcoplasmic reticulum Ca2+-release, and re-activation of ICa,L that trigger early afterdepolarizations (EADs) and TdP...
January 9, 2018: Heart Rhythm: the Official Journal of the Heart Rhythm Society
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