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https://www.readbyqxmd.com/read/28238947/identification-of-novel-mrp3-inhibitors-based-on-computational-models-and-validation-using-an-in-vitro-membrane-vesicle-assay
#1
Izna Ali, Matthew A Welch, Yang Lu, Peter W Swaan, Kim L R Brouwer
INTRODUCTION: Multidrug resistance-associated protein 3 (MRP3), an efflux transporter on the hepatic basolateral membrane, may function as a compensatory mechanism to prevent the accumulation of anionic substrates (e.g., bile acids) in hepatocytes. Inhibition of MRP3 may disrupt bile acid homeostasis and is one hypothesized risk factor for the development of drug-induced liver injury (DILI). Therefore, identifying potential MRP3 inhibitors could help mitigate the occurrence of DILI. METHODS: Bayesian models were developed using MRP3 transporter inhibition data for 86 structurally diverse drugs...
February 23, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28238945/nose-to-brain-transport-of-imatinib-mesylate-a-pharmacokinetic-evaluation
#2
Nobuko Hada, William Joseph Netzer, Fanny Belhassan, Lawrence Paul Wennogle, Sveinbjörn Gizurarson
The delivery of drugs to the brain is a constant challenge due to limitations imposed by the blood-brain barrier (BBB). Various methods of bypassing the BBB are under investigation. One approach is intranasal administration, where the olfactory region of the nasal cavity extends up to the cranial cavity and provides direct access to the brain. The pharmacokinetics of this transport and factors that determine transport rates and capacity is of vital importance for evaluating the clinical value of this route...
February 23, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28238899/estimation-of-the-contribution-of-cyp2c8-and-cyp3a4-in-repaglinide-metabolism-by-human-liver-microsomes-under-various-buffer-conditions
#3
Toshiyuki Kudo, Hitomi Goda, Yuki Yokosuka, Ryo Tanaka, Seina Komatsu, Kiyomi Ito
We have previously reported that the microsomal activities of CYP2C8 and CYP3A4 largely depend on the buffer condition used in in vitro metabolic studies, with different patterns observed between the two isozymes. In the present study, therefore, the possibility of buffer condition dependence of the fraction metabolized by CYP2C8 (fm2C8) for repaglinide, a dual substrate of CYP2C8 and CYP3A4, was estimated using human liver microsomes under various buffer conditions. Montelukast and ketoconazole showed a potent and concentration-dependent inhibition of CYP2C8-mediated paclitaxel 6α-hydroxylation and CYP3A4-mediated triazolam α-hydroxylation, respectively, without dependence on the buffer condition...
February 23, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28238727/testosterone-metabolism-of-equine-single-cyps-of-the-3a-subfamily-compared-to-the-human-cyp3a4
#4
S Vimercati, M Büchi, J Zielinski, N Peduto, M Mevissen
Cytochrome P450 enzymes (CYPs) are responsible for the phase I metabolism of drugs, xenobiotics and endogenous substances. Knowledge of single CYPs and their substrates is important for drug metabolism, helps to predict adverse effects and may prevent reduced drug efficacy in polypharmacy. In this study, three equine isoenzymes of the 3A subfamily, the equine flavoprotein NADPH-P450 oxidoreductase (POR), and the cytochrome b5 (CYB5) were cloned, sequenced and heterologously expressed in a baculovirus expression system...
February 23, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28238440/the-proteolytic-system-of-pineapple-stems-revisited-purification-and-characterization-of-multiple-catalytically-active-forms
#5
André Matagne, Laetitia Bolle, Rachida El Mahyaoui, Danielle Baeyens-Volant, Mohamed Azarkan
Crude pineapple proteases extract (aka stem bromelain; EC 3.4.22.4) is an important proteolytic mixture that contains enzymes belonging to the cysteine proteases of the papain family. Numerous studies have been reported aiming at the fractionation and characterization of the many molecular species present in the extract, but more efforts are still required to obtain sufficient quantities of the various purified protease forms for detailed physicochemical, enzymatic and structural characterization. In this work, we describe an efficient strategy towards the purification of at least eight enzymatic forms...
February 23, 2017: Phytochemistry
https://www.readbyqxmd.com/read/28238258/facile-colorimetric-detection-of-silver-ions-with-picomolar-sensitivity
#6
Zhuangqiang Gao, Grace G Liu, Haihang Ye, Robert Rauschendorfer, Dianping Tang, Xiaohu Xia
While various colorimetric methods have been actively developed for the detection of Ag+ ions due to the simplicity and reliability, their limits of detection are confined to the level of nanomolar (nM). Here, we demonstrate a novel strategy for colorimetric Ag+ detection with picomolar (pM) sensitivity. This strategy involves the use of polyvinylpyrrolidone (PVP)-capped Pt nanocubes as artificial peroxidases that can effectively generate color signal by catalyzing the oxidation of peroxidase substrates. In the presence of Ag+ ions, the color signal generated from such Pt cubes would be greatly diminished because of the specific and efficient inhibition of Ag+ toward the peroxidase-like activity of Pt cubes...
February 27, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28237904/anaerobic-digestion-of-sewage-sludge-with-grease-trap-sludge-and-municipal-solid-waste-as-co-substrates
#7
A Grosser, E Neczaj, B R Singh, Å R Almås, H Brattebø, M Kacprzak
The feasibility of simultaneous treatment of multiple wastes via co-digestion was studied in semi-continuous mode at mesophilic conditions. The obtained results indicated that sewage sludge, organic fraction of municipal waste (OFMSW) and grease trap sludge (GTS) possess complementary properties that can be combined for successful anaerobic digestion. During the co-digestion period, methane yield and VS removal were significantly higher in comparison to digestion of sewage sludge alone. Addition of GTS to digesters treating sewage sludge resulted in increased VS removal and methane yield up to 13% (from 50 to 56...
February 23, 2017: Environmental Research
https://www.readbyqxmd.com/read/28237711/pharmacological-inhibition-of-faah-modulates-tlr-induced-neuroinflammation-but-not-sickness-behaviour-an-effect-partially-mediated-by-central-trpv1
#8
Rebecca J Henry, Daniel M Kerr, Lisa E Flannery, Marykate Killilea, Edel M Hughes, Louise Corcoran, David P Finn, Michelle Roche
Aberrant activation of toll-like receptors (TLRs), key components of the innate immune system, has been proposed to underlie and exacerbate a range of central nervous system disorders. Increasing evidence supports a role for the endocannabinoid system in modulating inflammatory responses including those mediated by TLRs, and thus this system may provide an important treatment target for neuroinflammatory disorders. However, the effect of modulating endocannabinoid tone on TLR-induced neuroinflammation in vivo and associated behavioural changes is largely unknown...
February 22, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/28237650/inhibition-and-inactivation-of-human-cyp2j2-implications-in-cardiac-pathophysiology-and-opportunities-in-cancer-therapy
#9
REVIEW
Aneesh Karkhanis, Yanjun Hong, Eric Chun Yong Chan
Extrahepatic cytochrome P450 enzymes (CYP450) are pivotal in the metabolism of endogenous substrates and xenobiotics. CYP2J2 is a major cardiac CYP450 and primarily metabolizes polyunsaturated fatty acids such as arachidonic acid to cardioactive epoxyeicosatrienoic acids. Due to its role in endobiotic metabolism, CYP2J2 has been actively studied in recent years with the focus on its biological functions in cardiac pathophysiology. Additionally, CYP2J2 metabolizes a number of xenobiotics such as astemizole and terfenadine and is potently inhibited by danazol and telmisartan...
February 22, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28236969/glycogen-synthase-kinase-3-a-kinase-for-all-pathways
#10
Prital Patel, James R Woodgett
Glycogen synthase kinase-3 (GSK-3) is an unusual protein-serine kinase in that it is primarily regulated by inhibition and lies downstream of multiple cell signaling pathways. This raises a variety of questions in terms of its physiological role(s), how signaling specificity is maintained and why so many eggs have been placed into one basket. There are actually two baskets, as there are two isoforms, GSK-3α and β, that are highly related and largely redundant. Their many substrates range from regulators of cellular metabolism to molecules that control growth and differentiation...
2017: Current Topics in Developmental Biology
https://www.readbyqxmd.com/read/28236176/kinetics-of-interaction-between-substrates-substrate-analogs-and-benzoate-1-2-dioxygenase-from-benzoate-degrading-rhodococcus-opacus-1cp
#11
Inna P Solyanikova, Oksana V Borzova, Elena V Emelyanova
Benzoate 1,2-dioxygenase (BDO) of Rhodococcus opacus 1CP, which carried out the initial attack on benzoate, was earlier shown to be the enzyme with a narrow substrate specificity. A kinetics of interaction between benzoate 1,2-dioxygenase and substituted benzoates was assessed taking into account the enlarged list of the type of inhibition and using whole cells grown on benzoate. The type of inhibition was determined and the constants of a reaction of BDO with benzoate in the presence of 2-chlorobenzoate (2CBA), 3,5-dichlorobenzoate (3,5DCBA), and 3-methylbenzoate (3MBA) were calculated...
February 24, 2017: Folia Microbiologica
https://www.readbyqxmd.com/read/28235644/down-regulation-of-the-mitochondrial-aspartate-glutamate-carrier-isoform-1-agc1-inhibits-proliferation-and-n-acetylaspartate-synthesis-in-neuro2a-cells
#12
Emanuela Profilo, Luis Emiliano Peña-Altamira, Mariangela Corricelli, Alessandra Castegna, Alberto Danese, Gennaro Agrimi, Sabrina Petralla, Giulia Giannuzzi, Vito Porcelli, Luigi Sbano, Carlo Viscomi, Francesca Massenzio, Erika Mariana Palmieri, Carlotta Giorgi, Giuseppe Fiermonte, Marco Virgili, Luigi Palmieri, Massimo Zeviani, Paolo Pinton, Barbara Monti, Ferdinando Palmieri, Francesco Massimo Lasorsa
The mitochondrial aspartate-glutamate carrier isoform 1 (AGC1) catalyzes a Ca(2+)-stimulated export of aspartate to the cytosol in exchange for glutamate, and is a key component of the malate-aspartate shuttle which transfers NADH reducing equivalents from the cytosol to mitochondria. By sustaining the complete glucose oxidation, AGC1 is thought to be important in providing energy for cells, in particular in the CNS and muscle where this protein is mainly expressed. Defects in the AGC1 gene cause AGC1 deficiency, an infantile encephalopathy with delayed myelination and reduced brain N-acetylaspartate (NAA) levels, the precursor of myelin synthesis in the CNS...
February 21, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28235423/spatiotemporal-progression-of-ubiquitin-proteasome-system-inhibition-after-status-epilepticus-suggests-protective-adaptation-against-hippocampal-injury
#13
Tobias Engel, Jaime Martinez-Villarreal, Christine Henke, Eva M Jimenez-Mateos, Amaya Sanz-Rodriguez, Mariana Alves, Yasmina Hernandez-Santana, Gary P Brennan, Aidan Kenny, Aoife Campbell, Jose J Lucas, David C Henshall
BACKGROUND: The ubiquitin-proteasome-system (UPS) is the major intracellular pathway leading to the degradation of unwanted and/or misfolded soluble proteins. This includes proteins regulating cellular survival, synaptic plasticity and neurotransmitter signaling; processes controlling excitability thresholds that are altered by epileptogenic insults. Dysfunction of the UPS has been reported to occur in a brain region- and cell-specific manner and contribute to disease progression in acute and chronic brain diseases...
February 24, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28235422/crying-spells-triggered-by-thumb-index-rubbing-after-thalamic-stroke-a-case-report
#14
R Bassani, C Rosazza, L Ghirardin, V Caldiera, E Banco, C Casati, L Tesio
BACKGROUND: Pathologic crying, devoid of any emotional counterpart, is known to occur as a consequence of various brain stem, cortical hemispheric and cerebellar lesions or, quite exceptionally, of "dacrystic" epilepsy. The case reported here suggests that thalamic lesions may also cause crying spells, under the special circumstances described below. CASE PRESENTATION: After a mild left thalamic stroke a caucasian 77 years old man presented with crying spells with no emotional counterpart, triggered by thumb-index rubbing of his right hand...
February 24, 2017: BMC Research Notes
https://www.readbyqxmd.com/read/28231455/synthetic-investigation-physicochemical-characterization-and-antibacterial-evaluation-of-ternary-bi-iii-systems-with-hydroxycarboxylic-acid-and-aromatic-chelator-substrates
#15
C M Nday, E Halevas, A Tsiaprazi-Stamou, D Eleftheriadou, A Hatzidimitriou, G Jackson, D Reid, A Salifoglou
Due to its physical and chemical properties, bismuth (Bi(III)) is widely used in the treatment of several gastrointestinal and skin diseases, and infections caused by bacteria. Herein, its known antimicrobial potential was taken into consideration in the synthesis of two new hybrid ternary materials of Bi(III) with the physiological α-hydroxycarboxylic glycolic acid and 1,10-phenanthroline (phen), [Bi2(C2H2O3)2(C2H3O3)(NO3)]n(.) nH2O (1) and [Bi(C12H8N2)(NO3)4](C10H8N4) (2), aiming at improving its antibacterial properties...
February 11, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/28230174/a-hydrophobic-patch-surrounding-trp154-in-human-neuroserpin-controls-the-helix-f-dynamics-with-implications-in-inhibition-and-aggregation
#16
Mohammad Farhan Ali, Abhinav Kaushik, Charu Kapil, Dinesh Gupta, Mohamad Aman Jairajpuri
Neuroserpin (NS) mediated inhibition of tissue-type plasminogen activator (tPA) is important for brain development, synapse formation and memory. Aberrations in helix F and β-sheet A movement during inhibition can directly lead to epilepsy or dementia. Conserved W154 residue in a hydrophobic patch between helix F and β-sheet A is ideally placed to control their movement during inhibition. Molecular Dynamics (MD) simulation on wild type (WT) NS and its two variants (W154A and W154P) demonstrated partial deformation in helix F and conformational differences in strands 1A and 2A only in W154P...
February 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28228728/perivascular-adipose-tissue-s-impact-on-norepinephrine-induced-contraction-of-mesenteric-resistance-arteries
#17
Nadia Ayala-Lopez, Janice M Thompson, Stephanie W Watts
Background: Perivascular adipose tissue (PVAT) can decrease vascular contraction to NE. We tested the hypothesis that metabolism and/or uptake of vasoactive amines by mesenteric PVAT (MPVAT) could affect NE-induced contraction of the mesenteric resistance arteries. Methods: Mesenteric resistance vessels (MRV) and MPVAT from male Sprague-Dawley rats were used. RT-PCR and Western blots were performed to detect amine metabolizing enzymes. The Amplex® Red Assay was used to quantify oxidase activity by detecting the oxidase reaction product H2O2 and the contribution of PVAT on the mesenteric arteries' contraction to NE was measured by myography...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28228588/investigation-of-the-role-of-protein-kinase-d-in-human-rhinovirus-replication
#18
Anabel Guedán, Dawid Swieboda, Mark Charles, Marie Toussaint, Sebastian L Johnston, Amin Asfor, Anusha Panjwani, Tobias J Tuthill, Henry Danahay, Tony Raynham, Aurelie Mousnier, Roberto Solari
Picornavirus replication is known to cause extensive remodelling of Golgi and endoplasmic reticulum membranes and a number of the host proteins involved in the viral replication complex have been identified, including oxysterol binding protein (OSBP) and phosphatidylinositol 4-kinase III beta (PI4KB). Since both OSBP and PI4KB are substrates for protein kinase D (PKD) and PKD is known to be involved in the control of Golgi vesicular and lipid transport, we hypothesised that PKD played a role in viral replication...
February 22, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28228470/a-conditional-mutant-of-the-fatty-acid-synthase-unveils-unexpected-cross-talks-in-mycobacterial-lipid-metabolism
#19
Matías Cabruja, Sonia Mondino, Yi Ting Tsai, Julia Lara, Hugo Gramajo, Gabriela Gago
Unlike most bacteria, mycobacteria rely on the multi-domain enzyme eukaryote-like fatty acid synthase I (FAS I) to make fatty acids de novo. These metabolites are precursors of the biosynthesis of most of the lipids present both in the complex mycobacteria cell wall and in the storage lipids inside the cell. In order to study the role of the type I FAS system in Mycobacterium lipid metabolism in vivo, we constructed a conditional mutant in the fas-acpS operon of Mycobacterium smegmatis and analysed in detail the impact of reduced de novo fatty acid biosynthesis on the global architecture of the cell envelope...
February 2017: Open Biology
https://www.readbyqxmd.com/read/28228357/activation-of-mtor-i%C3%AE%C2%BAb-%C3%AE-nf-%C3%AE%C2%BAb-pathway-contributes-to-lps-induced-hypotension-and-inflammation-in-rats
#20
Meryem Temiz-Resitoglu, Sefika Pinar Kucukkavruk, Demet Sinem Guden, Pelin Cecen, Ayse Nihal Sari, Bahar Tunctan, Aysegul Gorur, Lulufer Tamer-Gumus, Cuneyt Kemal Buharalioglu, Kafait U Malik, Seyhan Sahan-Firat
Mammalian target of rapamycin (mTOR), a serine/threonine kinase plays an important role in various pathophysiological processes including cancer, metabolic diseases, and inflammation. Although mTOR participates in Toll-like receptor 4 signalling in different cell types, the role of this enzyme in sepsis pathogenesis and its effects on hypotension and inflammation in endotoxemic rats remains unclear. In this study we investigated the effects of mTOR inhibition on lipopolysaccharide (LPS)-induced changes on expressions and/or activities of ribosomal protein S6 (rpS6), an mTOR substrate, nuclear factor-κB (NF-κB) p65, inhibitor κB (IκB)-α, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 with production of nitric oxide, peroxynitrite, prostacyclin, and tumor necrosis factor (TNF)-α and activity of myeloperoxidase (MPO), which results in hypotension and inflammation...
February 20, 2017: European Journal of Pharmacology
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