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https://www.readbyqxmd.com/read/29138286/transporter-expression-in-non-cancerous-and-cancerous-liver-tissue-from-donors-with-hepatocellular-carcinoma-and-chronic-hepatitis-c-infection-quantified-by-lc-ms-ms-proteomics
#1
Sarah Billington, Adrian S Ray, Laurent Salphati, Guangqing Xiao, Xiaoyan Chu, W Griffith Humphreys, Mingxiang Liao, Caroline A Lee, Anita A Mathias, Cornelis E C A Hop, Christopher Rowbottom, Raymond Evers, Yurong Lai, Edward J Kelly, Bhagwat Prasad, Jashvant D Unadkat
Protein expression of major hepatobiliary drug transporters (NTCP, OATPs, OCT1, BSEP, BCRP, MATE1, MRPs and P-gp) in cancerous (C, n=8) and adjacent non-cancerous (NC, n=33) liver tissues obtained from chronic hepatitis C patients with hepatocellular carcinoma (HCV-HCC) were quantified by LC-MS/MS proteomics. Herein, we compare our results with our previous data from non-infected non-cirrhotic (control, n=36) and HCV-cirrhotic (n=30) livers. The amount of membrane protein yielded from NC and C HCV-HCC tissues decreased (31%, 67%) relative to control livers...
November 14, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29089306/organic-cation-transporter-1-is-responsible-for-hepatocellular-uptake-of-the-tyrosine-kinase-inhibitor-pazopanib
#2
Waleed Elsayed Ahmed Ellawatty, Yusuke Masuo, Ken-Ichi Fujita, Erina Yamazaki, Hiroo Ishida, Hiroshi Arakawa, Noritaka Nakamichi, Ramadan Abdelwahed, Yasutsuna Sasaki, Yukio Kato
Pazopanib is an orally active tyrosine kinase inhibitor that exhibits hepatotoxicity in some patients. Despite the clinical importance of its hepatic distribution, the transporter(s) responsible for hepatic uptake of pazopanib in humans remain undetermined. In order to characterize its hepatic uptake mechanism, we screened the effects of several transporter inhibitors, including tetrapentylammonium (TPeA) for organic cation transporters (OCTs) and cyclosporin A (CsA) for organic anion-transporting polypeptides (OATPs), on both plasma disappearance and hepatic distribution of pazopanib in mice after its intravenous administration...
October 31, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29080172/quantitative-trait-loci-for-root-growth-response-to-cadaverine-in-arabidopsis
#3
Nicole M Gibbs, Laura Vaughn Rouhana, Patrick H Masson
Root growth architecture is a major determinant of agricultural productivity and plant fitness in natural ecosystems. Here we describe the methods used in a Quantitative Trait Loci (QTL) study that allowed the identification of ORGANIC CATION TRANSPORTER 1 (OCT1) as a determinant of root growth response to cadaverine treatment in Arabidopsis thaliana. This protocol screens natural accessions to characterize the variation in root growth response to the naturally occurring polyamine cadaverine, then uses recombination mapping to identify loci that are responsible for the variation existing between two accessions with contrasting phenotypes...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29061131/proguanil-and-cycloguanil-are-organic-cation-transporter-and-multidrug-and-toxin-extrusion-substrates
#4
Maarten van der Velden, Albert Bilos, Jeroen J M W van den Heuvel, Sanna R Rijpma, Evelien G E Hurkmans, Robert W Sauerwein, Frans G M Russel, Jan B Koenderink
BACKGROUND: Malaria, HIV/AIDS, and tuberculosis endemic areas show considerable geographical overlap, leading to incidence of co-infections. This requires treatment with multiple drugs, potentially causing adverse drug-drug interactions (DDIs). As anti-malarials are generally positively charged at physiological pH, they are likely to interact with human organic cation transporters 1 and 2 (OCT1 and OCT2). These transporters are involved in the uptake of drugs into hepatocytes and proximal tubule cells for subsequent metabolic conversion or elimination...
October 23, 2017: Malaria Journal
https://www.readbyqxmd.com/read/29061087/oct1-pharmacogenetics-in-pain-management-is-a-clinical-application-within-reach
#5
Mladen V Tzvetkov
Beside drug metabolizing enzymes alsogenetically variable membrane transporters may substantially contribute to the interindividual variability in pharmacokinetics and efficacy of opioids and other analgesics. The organic cation transporter OCT1 is strongly expressed in the sinusoidal membrane of the human liver. It may affect hepatic uptake and thus limit metabolic rates. OCT1 is highly genetically variable. Genetic polymorphisms lead to substantially reduced OCT1 activity in up to 9% of the Europeans and the white Americans...
October 24, 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/29032766/the-effects-of-drug-metabolizing-enzyme-inhibitors-on-hepatic-efflux-and-uptake-transporters
#6
Jonathan Cheong, Jason S Halladay, Jasleen K Sodhi, Emile Plise, Laurent Salphati
BACKGROUND: Non-selective chemical inhibitors of phase I and phase II enzymes are commonly used in in vitro metabolic studies to elucidate the biotransformation pathways of drugs. However, the inhibition of the inhibitors on efflux and uptake transporters is not well investigated, potentially leading to unexpected and ambiguous results in these studies. OBJECTIVE: The commonly used metabolizing enzyme inhibitors, 1-aminobenzotriazole (ABT), SKF-525A, pargyline, allopurinol, menadione, methimazole, piperine and raloxifene, were examined for their potential inhibition of the major hepatic ABC (ATP binding cassette) and SLC (solute carrier) transporters...
October 10, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29019117/physiologically-based-pharmacokinetic-modeling-of-transporter-mediated-hepatic-clearance-and-liver-partitioning-of-oatp-and-oct-substrates-in-cynomolgus-monkeys
#7
Bridget L Morse, Jamus G MacGuire, Anthony M Marino, Yue Zhao, Maxine Fox, Yueping Zhang, Hong Shen, W Griffith Humphreys, Punit Marathe, Yurong Lai
In the present investigations, we evaluate in vitro hepatocyte uptake and partitioning for the prediction of in vivo clearance and liver partitioning. Monkeys were intravenously co-dosed with rosuvastatin and bosentan, substrates of the organic anion transporting polypeptides (OATPs), and metformin, a substrate of organic cation transporter 1 (OCT1). Serial plasma and liver samples were collected over time. Liver and plasma unbound fraction was determined using equilibrium dialysis. In vivo unbound partitioning (Kpu,u) for rosuvastatin, bosentan, and metformin, calculated from total concentrations in the liver and plasma, were 243, 553, and 15, respectively...
November 2017: AAPS Journal
https://www.readbyqxmd.com/read/28986476/colistin-is-substrate-of-the-carnitine-organic-cation-transporter-2-octn2-slc22a5
#8
Michele Visentin, Zhibo Gai, Angelo Torozi, Christian Hiller, Gerd A Kullak-Ublick
Colistin is a polycation antibiotic used for the treatment of multidrug-resistance (MDR) gram-negative infections; nevertheless, its use is often limited by the high incidence of renal damage. The mechanism underlying colistin-induced nephrotoxicity is not known, but perhaps related to its accumulation in the renal cortex upon extensive reabsorption from the nascent urine. Because little is known about the membrane transport of colistin, the purpose of the present study was to characterize better the transport system involved in colistin renal handling by using HEK293 cells stably transfected with the main organic cation transporters expressed at the apical membrane of the proximal tubule...
October 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28971610/mechanistic-in%C3%A2-vitro-studies-confirm-that-inhibition-of-the-renal-apical-efflux-transporter-multidrug-and-toxin-extrusion-mate-1-and-not-altered-absorption-underlies-the-increased-metformin-exposure-observed-in-clinical-interactions-with-cimetidine-trimethoprim
#9
Robert Elsby, Stephen Chidlaw, Samuel Outteridge, Sarah Pickering, Amy Radcliffe, Rebecca Sullivan, Hayley Jones, Philip Butler
Metformin is a common co-medication for many diseases and the victim of clinical drug-drug interactions (DDIs) perpetrated by cimetidine, trimethoprim and pyrimethamine, resulting in decreased active renal clearance due to inhibition of organic cation transport proteins and increased plasma exposure of metformin. To understand whether area under the plasma concentration-time curve (AUC) increases relate to absorption, in vitro inhibitory potencies of these drugs against metformin transport by human organic cation transporter (OCT) 1, and the apical to basolateral absorptive permeability of metformin across Caco-2 cells in the presence of therapeutic intestinal concentrations of cimetidine, trimethoprim or pyrimethamine, were determined...
October 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28955749/structure-organization-and-tissue-expression-of-the-pig-slc13a1-and-slc13a4-sulfate-transporter-genes
#10
Samuel K Barnes, Yvonne A Eiby, Soohyun Lee, Barbara E Lingwood, Paul A Dawson
Sulfate is an obligate nutrient for fetal growth and development. In mice, the renal Slc13a1 sulfate transporter maintains high maternal circulating levels of sulfate in pregnancy, and the placental Slc13a4 sulfate transporter mediates sulfate supply to the fetus. Both of these genes have been linked to severe embryonal defects and fetal loss in mice. However, the clinical significance of SLC13A1 and SLC13A4 in human gestation is unknown. One approach towards understanding the potential involvement of these genes in human fetal pathologies is to use an animal model, such as the pig, which mimics the developmental trajectory of the human fetus more closely than the previously studied mouse models...
July 2017: Biochemistry and Biophysics Reports
https://www.readbyqxmd.com/read/28947922/diabetes-medication-associates-with-dna-methylation-of-metformin-transporter-genes-in-the-human-liver
#11
Sonia García-Calzón, Alexander Perfilyev, Ville Männistö, Vanessa D de Mello, Emma Nilsson, Jussi Pihlajamäki, Charlotte Ling
BACKGROUND: Given that metformin is the most common pharmacological therapy for type 2 diabetes, understanding the function of this drug is of great importance. Hepatic metformin transporters are responsible for the pharmacologic action of metformin. However, epigenetics in genes encoding metformin transporters has not been fully elucidated. We examined the DNA methylation of these genes in the liver of subjects with type 2 diabetes and tested whether epigenetic alterations associate with diabetes medication, i...
2017: Clinical Epigenetics
https://www.readbyqxmd.com/read/28936218/atoma1-affects-the-oxphos-system-and-plant-growth-in-contrast-to-other-newly-identified-atp-independent-proteases-in-arabidopsis-mitochondria
#12
Iwona Migdal, Renata Skibior-Blaszczyk, Malgorzata Heidorn-Czarna, Marta Kolodziejczak, Arnold Garbiec, Hanna Janska
Compared with yeast, our knowledge on members of the ATP-independent plant mitochondrial proteolytic machinery is rather poor. In the present study, using confocal microscopy and immunoblotting, we proved that homologs of yeast Oma1, Atp23, Imp1, Imp2, and Oct1 proteases are localized in Arabidopsis mitochondria. We characterized these components of the ATP-independent proteolytic system as well as the earlier identified protease, AtICP55, with an emphasis on their significance in plant growth and functionality in the OXPHOS system...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28935584/vih-from-the-mud-crab-is-specifically-expressed-in-the-eyestalk-and-potentially-regulated-by-transactivator-of-sox9-oct4-oct1
#13
Chunyun Liu, Xiwei Jia, Zhihua Zou, Xiaowei Wang, Yilei Wang, Ziping Zhang
Vitellogenesis-inhibiting hormone (VIH) is known to regulate ovarian maturation by suppressing the synthesis of vitellogenin (Vtg) in crustaceans, which belongs to a member of crustacean hyperglycemic hormone (CHH) family synthesized and secreted from the X-organ/sinus gland complex of eyestalks. In this study, the cDNA, genomic DNA (gDNA) and the 5'-upstream regulatory (promoter region) sequences of VIH gene were obtained by conventional PCR, genome walker and tail-PCR techniques according to our transcriptomic database of Scylla paramamosain...
January 1, 2018: General and Comparative Endocrinology
https://www.readbyqxmd.com/read/28918032/microrna-31-regulates-chemosensitivity-in-malignant-pleural-mesothelioma
#14
Hannah L Moody, Michael J Lind, Stephen G Maher
Malignant pleural mesothelioma (MPM) is associated with an extremely poor prognosis, and most patients initially are or rapidly become unresponsive to platinum-based chemotherapy. MicroRNA-31 (miR-31) is encoded on a genomic fragile site, 9p21.3, which is reportedly lost in many MPM tumors. Based on previous findings in a variety of other cancers, we hypothesized that miR-31 alters chemosensitivity and that miR-31 reconstitution may influence sensitivity to chemotherapeutics in MPM. Reintroduction of miR-31 into miR-31 null NCI-H2452 cells significantly enhanced clonogenic resistance to cisplatin and carboplatin...
September 15, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28910443/spatiotemporally-controlled-ablation-of-klf5-results-in-dysregulated-epithelial-homeostasis-in-adult-mouse-corneas
#15
Chelsea L Loughner, Anil Tiwari, Doreswamy Kenchegowda, Sudha Swamynathan, Shivalingappa K Swamynathan
Purpose: Corneal epithelial (CE) homeostasis requires coordination between proliferation and differentiation. Here we examine the role of cell proliferation regulator Krüppel-like factor 5 (Klf5) in adult mouse CE homeostasis. Methods: Klf5 was ablated in a spatiotemporally restricted manner by inducing Cre expression in 8-week-old ternary transgenic Klf5LoxP/LoxP/Krt12rtTA/rtTA/Tet-O-Cre (Klf5Δ/ΔCE) mouse CE by administering doxycycline via chow. Normal chow-fed ternary transgenic siblings served as controls...
September 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28867436/effects-of-diosmetin-on-nine-cytochrome-p450-isoforms-ugts-and-three-drug-transporters-in-vitro
#16
Jun-Jun Chen, Jing-Xian Zhang, Xiang-Qi Zhang, Mei-Juan Qi, Mei-Zhi Shi, Jiao Yang, Ke-Zhi Zhang, Cheng Guo, Yong-Long Han
Diosmetin (3', 5, 7-trihydroxy-4'-methoxyflavone), a natural flavonoid from traditional Chinese herbs, has been used in various medicinal products because of its anticancer, antimicrobial, antioxidant, estrogenic and anti-inflammatory activity. However, flavonoids could affect the metabolic enzymes and cause drug-drug interactions (DDI), reducing the efficacy of co-administered drugs and potentially resulting in serious adverse reactions. To evaluate its potential to interact with co-administered drugs, the IC50 value of phase I cytochrome P450 enzymes (CYPs), phase II UDP-glucuronyltransferases (UGTs) and hepatic uptake transporters (organic cation transporters (OCTs), organic anion transporter polypeptides (OATPs) and Na(+)-taurocholate cotransporting polypeptides (NTCPs)) were examined in vitro by LC-MS/MS...
November 1, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28843219/molecular-response-to-imatinib-and-its-correlation-with-mrna-expression-levels-of-imatinib-influx-transporter-oct1-in-indian-chronic-myeloid-leukemia-patients
#17
S Chhikara, S Sazawal, T Seth, R Chaubey, K Singh, R Sharma, P Mishra, M Mahapatra, R Saxena
Background and objectives: Imatinib mesylate is approved for the treatment of Chronic Myeloid Leukemia (CML). About 20% of patients with CML do not respond to treatment with Imatinib either initially or because of acquired resistance. In addition to mutated BCR-ABL1 kinase, the organic cation transporter1 (OCT1, encoded by SLC22A1) has been considered to contribute to Imatinib resistance in patients with chronic myeloid leukemia (CML). OCT1 has been reported to be the main influx transporter involved in Imatinib uptake into CML cells...
August 27, 2017: Asian Pacific Journal of Cancer Prevention: APJCP
https://www.readbyqxmd.com/read/28834135/the-pharmacogenetics-of-metformin-in-women-with-polycystic-ovary-syndrome-a-randomized-trial
#18
Andreas J T Pedersen, Tore Bjerregaard Stage, Dorte Glintborg, Marianne Andersen, Mette Marie Hougaard Christensen
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. PCOS is associated with obesity, dyslipidaemia and insulin resistance, and metformin treatment may improve such metabolic features. The effect of genetic variants in key metformin transporters, their transcriptional regulators or in metformin target genes on metformin response in women with PCOS is unclear. Associations between pharmacodynamic responses to metformin (changes in weight, lipid profile, insulin sensitivity evaluated by oral glucose tolerance testing) and polymorphisms in OCT1 (rs12208357 and rs72552763), HNF1A (rs1169288 and rs2464196), MATE1 (rs2289669 and rs2252281), MATE2-K (rs12943590) and ATM (rs11212617) were studied in 40 women with PCOS randomized to 12 months of treatment with metformin 1000 mg twice daily ± oral contraceptive pills (150 μg desogestrel + 30 μg ethinylestradiol)...
August 21, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28821623/proteolytic-cleavage-by-the-inner-membrane-peptidase-imp-complex-or-oct1-peptidase-controls-the-localization-of-the-yeast-peroxiredoxin-prx1-to-distinct-mitochondrial-compartments
#19
Fernando Gomes, Flávio Romero Palma, Mario H Barros, Eduardo T Tsuchida, Helena G Turano, Thiago G P Alegria, Marilene Demasi, Luis E S Netto
Yeast Prx1 is a mitochondrial 1-Cys peroxiredoxin that catalyzes the reduction of endogenously generated H2O2 Prx1 is synthesized on cytosolic ribosomes as a preprotein with a cleavable N-terminal presequence that is the mitochondrial targeting signal, but the mechanisms underlying Prx1 distribution to distinct mitochondrial subcompartments are unknown. Here, we provide direct evidence of the following dual mitochondrial localization of Prx1: a soluble form in the intermembrane space and a form in the matrix weakly associated with the inner mitochondrial membrane...
October 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28800539/development-of-a-rapid-and-sensitive-multiple-reaction-monitoring-proteomic-approach-for-quantification-of-transporters-in-human-liver-tissue
#20
Li Wang, Kasi J Rubadue, Jeffrey Alberts, David W Bedwell, Kenneth J Ruterbories
With increasing knowledge on the role of hepatic transporters in drug disposition, numerous efforts have been described to quantify the expression of human hepatic transporters. However, reported quantitative proteomic approaches often require long analysis times. Additionally, greater assay sensitivity is still necessary for less abundant transporters or limited quantity of samples (e.g. hepatocytes and liver tissue). In the present study, an LC-MS/MS method for rapid and simultaneous quantification of 12 hepatic transporters (BCRP, BSEP, MATE1, MRP2, MRP3, MRP4, NTCP, OATP1B1, 1B3, 2B1, OCT1, and P-gp) was developed...
September 1, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
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