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https://www.readbyqxmd.com/read/29790415/a-gene-variant-near-atm-affects-the-response-to-metformin-and-metformin-plasma-levels-a-post-hoc-analysis-of-an-rct
#1
Mattijs Out, Matthijs L Becker, Ron H van Schaik, Philippe Lehert, Coen D Stehouwer, Adriaan Kooy
AIM: To determine the influence of polymorphisms on the effects of metformin on HbA1c, daily dose of insulin and metformin plasma concentration. Methods: In a post hoc analysis of a 4.3 year placebo-controlled randomized trial with 390 patients with Type 2 diabetes already on insulin, we analyzed the influence of polymorphisms in genes coding for ATM and the transporters OCT1 and MATE1. Outcome measures were a combined HbA1c + daily dose of insulin Z score and metformin plasma concentrations...
June 1, 2018: Pharmacogenomics
https://www.readbyqxmd.com/read/29735754/an-assessment-of-the-in-vitro-inhibition-of-cytochrome-p450-enzymes-cyp-udp-glucuronsyltransferases-ugt-and-transporters-by-phosphodiester-or-phosphorothioate-linked-oligonucleotides
#2
Faraz Kazmi, Phyllis Yerino, Chase McCoy, Andrew Parkinson, David B Buckley, Brian W Ogilvie
Oligonucleotides represent an expanding class of pharmacotherapeutics in development for various indications. Typically, oligonucleotides are developed with phosphorothioate linkages for the improvement of biological stability; however limited data are available on the potential of these molecules to cause drug-drug interactions (DDIs). In the present study, two non therapeutic oligonucleotides with either phosphodiester (PD-GP and PD-Ac) or phosphorothioate (PT-GP and PT-Ac) linkages were evaluated in vitro for their potential to inhibit P450s and UGTs in both human liver microsomes (HLM) and cryopreserved human hepatocytes (CHH) and to inhibit select transporters in expression systems...
May 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29684917/co2-permeability-of-rat-hepatocytes-and-relation-of-co2-permeability-to-co2-production
#3
Mariela Arias-Hidalgo, Qinggong Yuan, Fabrizio Carta, Claudiu T Supuran, Gerolf Gros, Volker Endeward
BACKGROUND/AIMS: It has been described that cells in culture with very low oxidative metabolism possess a low CO2 membrane permeability, PCO2, of ∼ 0.01 cm/s. On the other hand, cardiomyocytes and mitochondria with extremely high rates of O2 consumption exhibit very high CO2 membrane permeabilities of 0.1 and 0.3 cm/s, repectively. To ascertain that this represents a systematic relationship, we determine here PCO2 of hepatocytes, which exhibit an intermediate rate of O2 consumption...
2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29681543/the-pou-oct-transcription-factor-nubbin-controls-the-balance-of-intestinal-stem-cell-maintenance-and-differentiation-by-isoform-specific-regulation
#4
Xiongzhuo Tang, Yunpo Zhao, Nicolas Buchon, Ylva Engström
Drosophila POU/Oct transcription factors are required for many developmental processes, but their putative regulation of adult stem cell activity has not been investigated. Here, we show that Nubbin (Nub)/Pdm1, homologous to mammalian OCT1/POU2F1 and related to OCT4/POU5F1, is expressed in gut epithelium progenitor cells. We demonstrate that the nub-encoded protein isoforms, Nub-PB and Nub-PD, play opposite roles in the regulation of intestinal stem cell (ISC) maintenance and differentiation. Depletion of Nub-PB in progenitor cells increased ISC proliferation by derepression of escargot expression...
April 17, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29679469/influence-of-transporter-polymorphisms-on-drug-disposition-and-response-a-perspective-from-the-international-transporter-consortium
#5
Sook Wah Yee, Deanna J Brackman, Elizabeth A Ennis, Yuichi Sugiyama, Landry K Kamdem, Rebecca Blanchard, Aleksandra Galetin, Lei Zhang, Kathleen M Giacomini
Advances in genomic technologies have led to a wealth of information identifying genetic polymorphisms in membrane transporters, specifically how these polymorphisms affect drug disposition and response. This review describes the current perspective of the International Transporter Consortium (ITC) on clinically important polymorphisms in membrane transporters. ITC suggests that in addition to previously recommended polymorphisms in ABCG2 (BCRP) and SLCO1B1 (OATP1B1), polymorphisms in the emerging transporter, SLC22A1 (OCT1), be considered during drug development...
April 21, 2018: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29659562/organic-cation-transporter-1-oct1-modulates-multiple-cardiometabolic-traits-through-effects-on-hepatic-thiamine-content
#6
Xiaomin Liang, Sook Wah Yee, Huan-Chieh Chien, Eugene C Chen, Qi Luo, Ling Zou, Meiling Piao, Arias Mifune, Ligong Chen, Meredith E Calvert, Sarah King, Frode Norheim, Janna Abad, Ronald M Krauss, Kathleen M Giacomini
A constellation of metabolic disorders, including obesity, dysregulated lipids, and elevations in blood glucose levels, has been associated with cardiovascular disease and diabetes. Analysis of data from recently published genome-wide association studies (GWAS) demonstrated that reduced-function polymorphisms in the organic cation transporter, OCT1 (SLC22A1), are significantly associated with higher total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels and an increased risk for type 2 diabetes mellitus, yet the mechanism linking OCT1 to these metabolic traits remains puzzling...
April 2018: PLoS Biology
https://www.readbyqxmd.com/read/29627897/drug-drug-interaction-of-cefiderocol-a-siderophore-cephalosporin-via-human-drug-transporters
#7
Takayuki Katsube, Shiro Miyazaki, Yukitoshi Narukawa, Martha Hernandez-Illas, Toshihiro Wajima
PURPOSE: Cefiderocol, a siderophore cephalosporin, will be used concomitantly with other medications for treatment of bacterial infections. In vitro studies demonstrated inhibition potential of cefiderocol on organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 2-K, and organic anion transporting polypeptide (OATP) 1B3. The aim of this study was to assess in vivo drug-drug interaction (DDI) potential of cefiderocol using probe substrates for these transporters...
April 7, 2018: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29596446/gut-microbiota-varies-by-opioid-use-circulating-leptin-and-oxytocin-in-african-american-men-with-diabetes-and-high-burden-of-chronic-disease
#8
Elena Barengolts, Stefan J Green, Yuval Eisenberg, Arfana Akbar, Bharathi Reddivari, Brian T Layden, Lara Dugas, George Chlipala
OBJECTIVE: The gut microbiota is known to be related to type 2 diabetes (T2D), psychiatric conditions, and opioid use. In this study, we tested the hypothesis that variability in gut microbiota in T2D is associated with psycho-metabolic health. METHODS: A cross-sectional study was conducted among African American men (AAM) (n = 99) that were outpatients at a Chicago VA Medical Center. The main outcome measures included fecal microbiota ecology (by 16S rRNA gene sequencing), psychiatric disorders including opioid use, and circulating leptin and oxytocin as representative hormone biomarkers for obesity and psychological pro-social behavior...
2018: PloS One
https://www.readbyqxmd.com/read/29567937/imatinib-affects-the-expression-of-slc22a1-in-a-non-linear-concentration-dependent-manner-within-24-hours
#9
Sandhya Sreenivasan Tantuan, Christopher D Viljoen
BACKGROUND Imatinib is actively transported into cells by the organic cation transporter (OCT1), encoded by SLC22A1. As a result, the expression of SLC22A1 is considered a prognostic marker for treatment with imatinib in patients with chronic myeloid leukemia (CML). Although limited, there is conflicting evidence indicating that imatinib may affect the expression of SLC22A1. However, thus far, no studies have investigated the effect of imatinib on SLC22A1 expression in an imatinib-sensitive cell line, which would mimic a typical clinical setting...
March 23, 2018: Medical Science Monitor Basic Research
https://www.readbyqxmd.com/read/29534510/effects-of-honokiol-on-cyp450-activity-and-transporter-mrna-expression-in-type-2-diabetic-rats
#10
Junjun Wang, Ting Zhai, Yong Chen
This study was aimed to clarify the effect of honokiol (Hon) on the activity of Cytochrome P450 (CYP450) enzymes, and the level of mRNA expression of liver and kidney transporters in type 2 diabetic rats induced by high-fat diet and strepotozotocin. Rats were randomly divided into normal control (NC) group, diabetic control (DC) group and Hon groups ( n = 6). The activities of hepatic CYP1A2, CYP2E1, CYP2C, CYP2B, CYP3A and CYP4A, and the mRNA expression levels of hepatic and renal transporters, were determined...
March 12, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29518608/rip3-deficience-attenuates-potassium-oxonate-induced-hyperuricemia-and-kidney-injury
#11
Kang Wang, Lei Hu, Jian-Kang Chen
Recent preclinical and clinical evidence suggests that hyperuricemia (HU) is an independent risk factor for metabolic syndrome, hypertension, cardiovascular disease and chronic kidney disease. Receptor-interacting protein 3 (RIP3) is an important contributor in inducing programmed necrosis, representing a newly identified mechanism of cell death combining features of both apoptosis and necrosis. In our study, RIP3 was strongly expressed in mice with hyperuricemia. RIP3 deficiency attenuated hyperuricemia in mice, evidenced by reduced serum uric acid and creatinine and enhanced urinary uric acid and creatinine, as well as the improved histological alterations in renal sections...
May 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29510895/effect-of-abcg2-oct1-and-abcb1-mdr1-gene-expression-on-treatment-free-remission-in-a-euro-ski-subtrial
#12
Sébastien Rinaldetti, Markus Pfirrmann, Kirsi Manz, Joelle Guilhot, Christian Dietz, Panayiotidis Panagiotidis, Birgit Spiess, Wolfgang Seifarth, Alice Fabarius, Martin Müller, Maria Pagoni, Maria Dimou, Jolanta Dengler, Cornelius F Waller, Tim H Brümmendorf, Regina Herbst, Andreas Burchert, Carsten Janβen, Maria Elisabeth Goebeler, Philipp J Jost, Stefan Hanzel, Philippe Schafhausen, Gabriele Prange-Krex, Thomas Illmer, Viktor Janzen, Martine Klausmann, Robert Eckert, Gerd Büschel, Alexander Kiani, Wolf-Karsten Hofmann, François-Xavier Mahon, Susanne Saussele
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. MATERIALS AND METHODS: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial...
April 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29506983/liver-zonation-index-of-drug-transporter-and-metabolizing-enzyme-protein-expressions-in-mouse-liver-acinus
#13
Masanori Tachikawa, Yuna Sumiyoshiya, Daisuke Saigusa, Kazunari Sasaki, Michitoshi Watanabe, Yasuo Uchida, Tetsuya Terasaki
The purpose of the present study was to clarify the molecular basis of zonated drug distributions in mouse liver based on the protein expression levels of transporters and metabolizing enzymes in periportal (PP) and pericentral (PC) vein regions of mouse hepatic lobules. The distributions of sulforhodamine 101 (SR-101), a substrate of organic anion transporting polypeptides (Oatps), and ribavirin, a substrate of equilibrative nucleoside transporter 1 (Ent1), were elucidated in frozen liver sections of mice, to which each compound had been intravenously administered...
May 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29494619/shared-activity-patterns-arising-at-genetic-susceptibility-loci-reveal-underlying-genomic-and-cellular-architecture-of-human-disease
#14
J Kenneth Baillie, Andrew Bretherick, Christopher S Haley, Sara Clohisey, Alan Gray, Lucile P A Neyton, Jeffrey Barrett, Eli A Stahl, Albert Tenesa, Robin Andersson, J Ben Brown, Geoffrey J Faulkner, Marina Lizio, Ulf Schaefer, Carsten Daub, Masayoshi Itoh, Naoto Kondo, Timo Lassmann, Jun Kawai, Damian Mole, Vladimir B Bajic, Peter Heutink, Michael Rehli, Hideya Kawaji, Albin Sandelin, Harukazu Suzuki, Jack Satsangi, Christine A Wells, Nir Hacohen, Thomas C Freeman, Yoshihide Hayashizaki, Piero Carninci, Alistair R R Forrest, David A Hume
Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA)...
March 2018: PLoS Computational Biology
https://www.readbyqxmd.com/read/29486427/pharmacogenetics-and-target-identification-in-diabetes
#15
REVIEW
Ewan R Pearson
In diabetes, pharmacogenetics can be used both to identify patient subgroups who will have most benefit and/or least harm from a particularly treatment, and to gain insights into the molecular mechanisms of drug action and disease aetiology. There is increasing evidence that genetic variation alters response to diabetes treatments-both in terms of glycaemic response and side effects. This can be seen with dramatic impact on clinical care, in patients with genetic forms of diabetes such as Maturity Onset Diabetes of the Young caused by HNF1A mutations, and Neonatal diabetes due to activating mutations in ABCC8 or KCNJ11...
February 24, 2018: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/29480578/houttuynia-cordata-extract-increased-systemic-exposure-and-liver-concentrations-of-metformin-through-octs-and-mates-in-rats
#16
Byoung Hoon You, Young-Won Chin, Hojun Kim, Han Seok Choi, Young Hee Choi
The synergistic activity of Houttuynia cordata ethanol extract (HCT) and metformin combination in diabetic rats has been previously reported, but the fundamental causes remain unsolved. Organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs) transport metformin to the liver and kidneys. Therefore, pharmacological activity and systemic exposure of metformin in HCT-metformin combination were determined from pharmacokinetic change and glucose-lowering activity using in vitro HEK-293 cells expressing human OCTs or human MATEs and in vivo rats...
February 26, 2018: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/29448871/interactions-of-organophosphorus-pesticides-with-solute-carrier-slc-drug-transporters
#17
Lisa Chedik, Arnaud Bruyere, Olivier Fardel
1. Organophosphorus pesticides (OPs) are known to interact with human ATP-binding cassette drug efflux pumps. The present study was designed to determine whether they can also target activities of human solute carrier (SLC) drug transporters. 2. The interactions of 13 OPs with SLC transporters involved in drug disposition, such as organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), organic anion transporters (OATs) and organic anion transporting polypeptides (OATPs), were mainly investigated using transporter-overexpressing cell clones and fluorescent or radiolabeled reference substrates...
March 6, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29439128/comparison-of-proteomic-quantification-approaches-for-hepatic-drug-transporters-multiplexed-global-quantitation-correlates-with-targeted-proteomic-quantitation
#18
Anna Vildhede, Chuong Nguyen, Brian K Erickson, Ryan C Kunz, Richard Jones, Emi Kimoto, Francis Bourbonais, A David Rodrigues, Manthena V S Varma
Targeted protein quantification using liquid chromatography-tandem mass spectrometry with stable isotope-labeled standards is recognized as the gold standard of practice for protein quantification. Such assays, however, can only cover a limited number of proteins, and developing targeted methods for larger numbers of proteins requires substantial investment. Alternatively, large-scale global proteomic experiments along with computational methods such as the "total protein approach" (TPA) have the potential to provide extensive protein quantification...
May 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29417972/relevance-of-copper-transporter-1-and-organic-cation-transporters-1-3-for-oxaliplatin-uptake-and-drug-resistance-in-colorectal-cancer-cells
#19
I Buß, A Hamacher, N Sarin, M U Kassack, G V Kalayda
Oxaliplatin is a routinely used drug in the treatment of colorectal cancer. However, development of resistance is a major hurdle of the chemotherapy success. Defects in cellular accumulation represent a frequently reported feature of cells with acquired resistance to platinum drugs. Nevertheless, the mechanisms of oxaliplatin uptake and their role in oxaliplatin resistance remain poorly elucidated. The aim of this study was to investigate the relevance of copper transporter 1 (CTR1) and organic cation transporters 1-3 (OCT1-3) for oxaliplatin uptake and resistance to the drug in sensitive and oxaliplatin-resistant ileocecal colorectal adenocarcinoma cells...
March 1, 2018: Metallomics: Integrated Biometal Science
https://www.readbyqxmd.com/read/29352482/influence-of-pharmacogenetic-polymorphisms-and-demographic-variables-on-metformin-pharmacokinetics-in-an-admixed-brazilian-cohort
#20
Ana Beatriz Santoro, Mariana Rodrigues Botton, Claudio José Struchiner, Guilherme Suarez-Kurtz
AIMS: To identify pharmacogenetic and demographic variables that influence the systemic exposure to metformin in an admixed Brazilian cohort. METHODS: The extreme discordant phenotype was used to select 106 data sets from nine metformin bioequivalence trials, comprising 256 healthy adults. Eleven single-nucleotide polymorphisms in SLC22A1, SLC22A2, SLC47A1 SLC47A2 and in transcription factor SP1 were genotyped and a validated panel of ancestry informative markers was used to estimate the individual proportions of biogeographical ancestry...
May 2018: British Journal of Clinical Pharmacology
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