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https://www.readbyqxmd.com/read/28626473/clinical-applicability-of-whole-exome-sequencing-exemplified-by-a-study-in-young-adults-with-the-advanced-cryptogenic-cholestatic-liver-diseases
#1
Maria Kulecka, Andrzej Habior, Agnieszka Paziewska, Krzysztof Goryca, Michalina Dąbrowska, Filip Ambrozkiewicz, Bożena Walewska-Zielecka, Andrzej Gabriel, Michal Mikula, Jerzy Ostrowski
BACKGROUND: The proper use of new medical tests in clinical practice requires the establishment of their value and range of diagnostic usefulness. While whole-exome sequencing (WES) has already entered the medical practice, recognizing its diagnostic usefulness in multifactorial diseases has not yet been achieved. AIMS: The objective of this study was to establish usability of WES in determining genetic background of chronic cholestatic liver disease (CLD) in young patients...
2017: Gastroenterology Research and Practice
https://www.readbyqxmd.com/read/28583112/clinical-and-genetic-factors-associated-with-kidney-tubular-dysfunction-in-a-real-life-single-centre-cohort-of-hiv-positive-patients
#2
S E Salvaggio, A Giacomelli, F S Falvella, M L Oreni, P Meraviglia, C Atzori, E G I Clementi, M Galli, S Rusconi
BACKGROUND: Tenofovir (TDF) is one of the most widely used antiretroviral drug. Despite the high degree of tolerability a small percentage of patients experienced alteration in tubular function during TDF use. Intracellular TDF disposition is regulated by ATP-binding cassette (ABC) drug efflux transporters and, a reduced transport activity may be implicated in accumulation of TDF into the cells. The aim of our study was to assess the major determinants of TDF associated tubular dysfunction (KTD) in a real-life setting including the usefulness of single-nucleotide polymorphisms (SNPs) mapping into ABCC2, ABCC4 and ABCC10 genes...
June 5, 2017: BMC Infectious Diseases
https://www.readbyqxmd.com/read/28550450/abcc4-functional-snp-in-the-3-splice-acceptor-site-of-exon-8-g912t-is-associated-with-unfavorable-clinical-outcome-in-children-with-acute-lymphoblastic-leukemia
#3
Hamzeh Mesrian Tanha, Soheila Rahgozar, Marjan Mojtabavi Naeini
OBJECTIVES: ATP-binding cassette subfamily C member 4 (ABCC4) encoding MRP4 protein is involved in pediatric acute lymphoblastic leukemia (ALL) drug resistance. The nonsynonymous single nucleotide polymorphism (SNP) rs2274407 (G912T; K304N) is located in the 3' splice acceptor site of exon 8 of ABCC4 pre-mRNA. The aim of this study was to investigate the prognostic value of rs2274407 in childhood ALL and its possible functional effect on MRP4. METHODS: ABCC4 G912T SNP was genotyped in 145 Iranian Philadelphia-negative (Ph(-)) children with ALL using modified tetra-primer ARMS PCR and evaluated for possible association with 3-year disease-free survival (3DFS)...
May 26, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28456721/investigation-of-the-importance-of-multidrug-resistance-associated-protein-4-mrp4-abcc4-in-the-active-efflux-of-anionic-drugs-across-the-blood-brain-barrier
#4
Kayoko Kanamitsu, Hiroyuki Kusuhara, John D Schuetz, Kenji Takeuchi, Yuichi Sugiyama
The importance of multidrug resistance-associated protein 4 (Mrp4/Abcc4) in limiting the penetration of Mrp4 substrate compounds into the central nervous system across the blood-brain barrier was investigated using Mrp4(-/-) mice. Significant adenosine triphosphate-dependent uptake by MRP4 was observed for ochratoxin A, pitavastatin, raltitrexed (Km = 43.7 μM), pravastatin, cyclic guanosine monophosphate, 2,4-dichlorophenoxyacetate, and urate. The defect in the Mrp4 gene did not affect the brain-to-plasma ratio (Kp,brain) of quinidine and dantrolene...
April 27, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28418010/interaction-between-nudt15-and-abcc4-variants-enhances-intolerability-of-6-mercaptopurine-in-japanese-patients-with-childhood-acute-lymphoblastic-leukemia
#5
Y Tanaka, H Nakadate, K Kondoh, K Nakamura, K Koh, A Manabe
6-Mercaptopurine (6-MP) is a main component of childhood acute lymphoblastic leukemia (ALL) treatment. Some candidate gene variants are associated with its toxicities, but the major variants and effects of combined variants remain unclear. We used Cox regression analysis to evaluate the time-dependent association between candidate variants and the cumulative incidence of 6-MP intolerability in 95 Japanese patients. The major risk factors for severe leukopenia were ABCC4 rs3765534, NUDT15 rs116855232 and rs186364861 in multi-covariate analysis (P<0...
April 18, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28371506/population-specific-resequencing-associates-the-atp-binding-cassette-subfamily-c-member-4-gene-with-gout-in-new-zealand-m%C3%A4-ori-and-pacific-men
#6
Callum Tanner, James Boocock, Eli A Stahl, Amanda Dobbyn, Asim K Mandal, Murray Cadzow, Amanda J Phipps-Green, Ruth K Topless, Jennie Harré Hindmarsh, Lisa K Stamp, Nicola Dalbeth, Hyon K Choi, David B Mount, Tony R Merriman
OBJECTIVE: There is no evidence for a genetic association between organic anion transporters 1-3 (SLC22A6, SLC22A7, and SLC22A8) and multidrug resistance protein 4 (MRP4; encoded by ABCC4) with the levels of serum urate or gout. The Māori and Pacific (Polynesian) population of New Zealand has the highest prevalence of gout worldwide. The aim of this study was to determine whether any Polynesian population-specific genetic variants in SLC22A6-8 and ABCC4 are associated with gout. METHODS: All participants had ≥3 self-reported Māori and/or Pacific grandparents...
March 28, 2017: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/28298215/nrf2-signaling-increases-expression-of-atp-binding-cassette-subfamily-c-mrna-transcripts-at-the-blood-brain-barrier-following-hypoxia-reoxygenation-stress
#7
Kathryn Ibbotson, Joshua Yell, Patrick T Ronaldson
BACKGROUND: Strategies to maintain BBB integrity in diseases with a hypoxia/reoxygenation (H/R) component involve preventing glutathione (GSH) loss from endothelial cells. GSH efflux transporters include multidrug resistance proteins (Mrps). Therefore, characterization of Mrp regulation at the BBB during H/R is required to advance these transporters as therapeutic targets. Our goal was to investigate, in vivo, regulation of Abcc1, Abcc2, and Abcc4 mRNA expression (i.e., genes encoding Mrp isoforms that transport GSH) by nuclear factor E2-related factor (Nrf2) using a well-established H/R model...
March 16, 2017: Fluids and Barriers of the CNS
https://www.readbyqxmd.com/read/28274777/impact-of-endotoxin-on-the-expression-of-drug-transporters-in-the-placenta-of-hiv-1-transgenic-hiv-tg-rats
#8
Ragia H Ghoneim, Dea Kojovic, Micheline Piquette-Miller
BACKGROUND: Inflammatory responses in HIV (+) patients may be exacerbated due to reports of subclinical endotoxemia and existing immune dysregulation. As inflammation has been reported to mediate changes in the expression of transporters, this could be potentiated in pregnant HIV (+) women. Similar to humans, the HIV-Tg rat model develops immune dysregulation and chronic AIDS-like conditions. Our objective was to examine the expression of placental drug transporters in HIV-Tg rats in response to low-dose endotoxin...
March 6, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28254523/transcriptomic-analysis-and-plasma-metabolomics-in-aldh16a1-null-mice-reveals-a-potential-role-of-aldh16a1-in-renal-function
#9
Georgia Charkoftaki, Ying Chen, Ming Han, Monica Sandoval, Xiaoqing Yu, Hongyu Zhao, David J Orlicky, David C Thompson, Vasilis Vasiliou
ALDH16A1 is a novel member of the ALDH superfamily that is enzymatically-inactive and highly expressed in the kidney. Recent studies identified an association between a rare missense single nucleotide variant (SNV) in the ALDH16A1 gene and elevated serum uric acid levels and gout. The present study explores the mechanisms by which ALDH16A1 influences uric acid homeostasis in the kidney. We generated and validated a mouse line with global disruption of the Aldh16a1 gene through gene targeting and performed RNA-seq analyses in the kidney of wild-type (WT) and Aldh16a1 knockout (KO) mice, along with plasma metabolomics...
February 28, 2017: Chemico-biological Interactions
https://www.readbyqxmd.com/read/28249282/progress-in-the-molecular-characterization-of-hepatobiliary-transporters
#10
REVIEW
Dietrich Keppler
Over the last 25 years, our understanding of the driving forces for hepatobiliary elimination and knowledge of the molecular basis of uptake and efflux transport in hepatocytes have undergone fundamental changes. This refers to bile acids and many other endogenous substances as well as to drugs that are eliminated on the hepatobiliary route. In this development, not only molecular cloning, functional characterization, and localization of transporters were decisive, but also the discovery of hereditary mutations in genes encoding sinusoidal uptake transporters and canalicular export pumps in humans and rodents...
2017: Digestive Diseases
https://www.readbyqxmd.com/read/28042832/r-flurbiprofen-traps-prostaglandins-within-cells-by-inhibition-of-multidrug-resistance-associated-protein-4
#11
Ivonne Wobst, Lisa Ebert, Kerstin Birod, Marthe-Susanna Wegner, Marika Hoffmann, Dominique Thomas, Carlo Angioni, Michael J Parnham, Dieter Steinhilber, Irmgard Tegeder, Gerd Geisslinger, Sabine Grösch
R-flurbiprofen is the non-COX-inhibiting enantiomer of flurbiprofen and is not converted to S-flurbiprofen in human cells. Nevertheless, it reduces extracellular prostaglandin E₂ (PGE₂) in cancer or immune cell cultures and human extracellular fluid. Here, we show that R-flurbiprofen acts through a dual mechanism: (i) it inhibits the translocation of cPLA2α to the plasma membrane and thereby curtails the availability of arachidonic acid and (ii) R-flurbiprofen traps PGE₂ inside of the cells by inhibiting multidrug resistance-associated protein 4 (MRP4, ABCC4), which acts as an outward transporter for prostaglandins...
December 30, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28011504/prognostic-and-therapeutic-potential-implications-of-genetic-variability-in-prostaglandin-e2-pathway-genes-in-rectal-cancer
#12
Marisa D Santos, Cristina Silva, Anabela Rocha, Carlos Nogueira, Fernando Castro-Poças, António Araujo, Eduarda Matos, Carina Pereira, Rui Medeiros, Carlos Lopes
AIM: To evaluate the prognostic significance and potential therapeutic implication of genetic variability in prostaglandin E2 pathway genes in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT) followed by surgery. MATERIALS AND METHODS: This cohort study included 167 patients with LARC, treated with nCRT followed by surgery. A total of 61 single nucleotide polymorphisms (SNPs) were characterized using the Sequenom platform through multiplex amplification followed by mass-spectometric product separation...
2017: Anticancer Research
https://www.readbyqxmd.com/read/27941536/lc-ms-ms-analysis-of-erythrocyte-thiopurine-nucleotides-and-their-association-with-genetic-variants-in-patients-with-neuromyelitis-optica-spectrum-disorders-taking-azathioprine
#13
Shenghui Mei, Xindi Li, Xiaoqing Gong, Xingang Li, Li Yang, Heng Zhou, Yonghong Liu, Anna Zhou, Leting Zhu, Xinghu Zhang, Zhigang Zhao
BACKGROUND: Azathioprine is a first-line drug in treating neuromyelitis optica spectrum disorders (NMOSD). To exhibit its bioactivity, azathioprine needs to be converted to thiopurine nucleotides (TPNs) including 6-thioguanine nucleotides (6-TGNs) and 6-methylmercaptopurine nucleotides (6-MMPNs) that are affected by genetic polymorphisms. This study aims to develop an LC-MS/MS method for the analysis of erythrocyte concentrations of TPNs and to evaluate their associations with variants of various genes (MTHFR, TPMT, HLA, SLC29A1, SLC28A2, SLC28A3, ABCB1, and ABCC4) in patients with NMOSD...
February 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/27895309/hepatocyte-specific-expression-of-an-oncogenic-variant-of-%C3%AE-catenin-results-in-cholestatic-liver-disease
#14
Ursula J Lemberger, Claudia D Fuchs, Matthias Karer, Stefanie Haas, Tatjana Stojakovic, Christian Schöfer, Hanns-Ulrich Marschall, Fritz Wrba, Makoto M Taketo, Gerda Egger, Michael Trauner, Christoph H Österreicher
BACKGROUND: The Wnt/β-catenin signaling pathway plays a crucial role in embryonic development, tissue homeostasis, wound healing and malignant transformation in different organs including the liver. The consequences of continuous β-catenin signaling in hepatocytes remain elusive. RESULTS: Livers of Ctnnb1CA hep mice were characterized by disturbed liver architecture, proliferating cholangiocytes and biliary type of fibrosis. Serum ALT and bile acid levels were significantly increased in Ctnnb1CA hep mice...
December 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27809359/renal-function-in-hiv-hbv-coinfected-and-hbv-monoinfected-patients-on-a-long-term-treatment-with-tenofovir-in-real-life-setting
#15
Laura Milazzo, Cristina Gervasoni, Felicia Stefania Falvella, Dario Cattaneo, Cristina Mazzali, Paola Ronzi, Francesca Binda, Stefania Cheli, Salvatore Sollima, Spinello Antinori
The HIV/HBV coinfection is likely associated with increased risk of kidney disease, due to the additional factors that may affect renal function in the HIV population. We aimed to evaluate renal toxicity in HIV/HBV and HBV monoinfected patients on long-term therapy with tenofovir (TDF) and to explore the association of polymorphisms in ATP-binding cassette (ABCC)2, ABCC4, ABCC10 with the development of renal dysfunction. From September 2006 to November 2014, 44 HIV/HBV co-infected and 34 HBV monoinfected patients were commenced on TDF...
November 3, 2016: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/27764917/expression-and-regulation-of-prostaglandin-transporters-atp-binding-cassette-subfamily-c-member-1-and-9-and-solute-carrier-organic-anion-transporter-family-member-2a1-and-5a1-in-the-uterine-endometrium-during-the-estrous-cycle-and-pregnancy-in-pigs
#16
Hwanhee Jang, Yohan Choi, Inkyu Yoo, Jisoo Han, Minjeong Kim, Hakhyun Ka
OBJECTIVE: Prostaglandins (PGs) function in various reproductive processes, including luteolysis, maternal pregnancy recognition, conceptus development, and parturition. Our earlier study has shown that PG transporters ATP-binding cassette, subfamily C, member 4 (ABCC4) and solute carrier organic anion transporter family, member 2A1 (SLCO2A1) are expressed in the uterine endometrium in pigs. Since several other PG transporters such as ABCC1, ABCC9, SLCO4C1, and SLCO5A1 are known to be present in the uterine endometrium, this study investigated the expression of these PG transporters in the porcine uterine endometrium and placenta...
May 2017: Asian-Australasian Journal of Animal Sciences
https://www.readbyqxmd.com/read/27761583/several-adaptor-proteins-promote-intracellular-localisation-of-the-transporter-mrp4-abcc4-in-platelets-and-haematopoietic-cells
#17
Yvonne Schaletzki, Marie-Luise Kromrey, Susanne Bröderdorf, Elke Hammer, Markus Grube, Paul Hagen, Sonja Sucic, Michael Freissmuth, Uwe Völker, Andreas Greinacher, Bernhard H Rauch, Heyo K Kroemer, Gabriele Jedlitschky
The multidrug resistance protein 4 (MRP4/ABCC4) has been identified as an important transporter for signalling molecules including cyclic nucleotides and several lipid mediators in platelets and may thus represent a novel target to interfere with platelet function. Besides its localisation in the plasma membrane, MRP4 has been also detected in the membrane of dense granules in resting platelets. In polarised cells it is localised at the basolateral or apical plasma membrane. To date, the mechanism of MRP4 trafficking has not been elucidated; protein interactions may regulate both the localisation and function of this transporter...
October 20, 2016: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/27664577/characterization-of-acquired-paclitaxel-resistance-of-breast-cancer-cells-and-involvement-of-abc-transporters
#18
Vlasta Němcová-Fürstová, Dana Kopperová, Kamila Balušíková, Marie Ehrlichová, Veronika Brynychová, Radka Václavíková, Petr Daniel, Pavel Souček, Jan Kovář
Development of taxane resistance has become clinically very important issue. The molecular mechanisms underlying the resistance are still unclear. To address this issue, we established paclitaxel-resistant sublines of the SK-BR-3 and MCF-7 breast cancer cell lines that are capable of long-term proliferation in 100nM and 300nM paclitaxel, respectively. Application of these concentrations leads to cell death in the original counterpart cells. Both sublines are cross-resistant to doxorubicin, indicating the presence of the MDR phenotype...
November 1, 2016: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/27659809/polymorphic-variants-of-mrp4-abcc4-differentially-modulate-the-transport-of-methylated-arsenic-metabolites-and-physiological-organic-anions
#19
COMPARATIVE STUDY
Mayukh Banerjee, Vanessa Marensi, Gwenaëlle Conseil, X Chris Le, Susan P C Cole, Elaine M Leslie
Broad inter-individual variation exists in susceptibility to arsenic-induced tumours, likely involving differences in the ability of individuals to eliminate this metalloid. We recently identified human multidrug resistance protein 4 (MRP4/ABCC4) as a novel pathway for the cellular export of dimethylarsinic acid (DMA(V)), the major urinary arsenic metabolite in humans, and the diglutathione conjugate of the highly toxic monomethylarsonous acid [MMA(GS)2]. These findings, together with the basolateral and apical membrane localization of MRP4 in hepatocytes and renal proximal tubule cells, respectively, suggest a role for MRP4 in the urinary elimination of hepatic arsenic metabolites...
November 15, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27649261/mir-pharmacogenetics-of-methotrexate-in-childhood-b-cell-acute-lymphoblastic-leukemia
#20
Leire Iparraguirre, Angela Gutierrez-Camino, Maitane Umerez, Idoia Martin-Guerrero, Itziar Astigarraga, Aurora Navajas, Ana Sastre, Nagore Garcia de Andoin, Africa Garcia-Orad
OBJECTIVES: Methotrexate (MTX), the key drug in childhood B-cell acute lymphoblastic leukemia (B-ALL) therapy, often causes toxicity. An association between genetic variants in MTX transport genes and toxicity has been found. It is known that these transporters are regulated by microRNAs (miRNAs), and miRNA single nucleotide polymorphisms (SNPs) interfere with miRNA levels or function. With regard to B-cell ALL, we have previously found rs56103835 in miR-323b that targets ABCC4 associated with MTX plasma levels...
November 2016: Pharmacogenetics and Genomics
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