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https://www.readbyqxmd.com/read/29145976/not-only-p-glycoprotein-amplification-of-the-abcb1-containing-chromosome-region-7q21-confers-multidrug-resistance-upon-cancer-cells-by-coordinated-overexpression-of-an-assortment-of-resistance-related-proteins
#1
Ilaria Genovese, Andrea Ilari, Yehuda G Assaraf, Francesco Fazi, Gianni Colotti
The development of drug resistance continues to be a dominant hindrance toward curative cancer treatment. Overexpression of a wide-spectrum of ATP-dependent efflux pumps, and in particular of ABCB1 (P-glycoprotein or MDR1) is a well-known resistance mechanism for a plethora of cancer chemotherapeutics including for example taxenes, anthracyclines, Vinca alkaloids, and epipodopyllotoxins, demonstrated by a large array of published papers, both in tumor cell lines and in a variety of tumors, including various solid tumors and hematological malignancies...
May 2017: Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
https://www.readbyqxmd.com/read/28924228/an-expanded-role-for-heterozygous-mutations-of-abcb4-abcb11-atp8b1-abcc2-and-tjp2-in-intrahepatic-cholestasis-of-pregnancy
#2
Peter H Dixon, Melissa Sambrotta, Jennifer Chambers, Pamela Taylor-Harris, Argyro Syngelaki, Kypros Nicolaides, A S Knisely, Richard J Thompson, Catherine Williamson
Intrahepatic cholestasis of pregnancy (ICP) affects 1/140 UK pregnancies; with pruritus, hepatic impairment and elevated serum bile acids. Severe disease is complicated by spontaneous preterm delivery and stillbirth. Previous studies have reported mutations in hepatocellular transporters (ABCB4, ABCB11). High throughput sequencing in 147 patients was performed in the transporters ABCB4, ABCB11, ATP8B1, ABCC2 and tight junction protein 2 (TJP2). Twenty-six potentially damaging variants were identified with the following predicted protein changes: Twelve ABCB4 mutations - Arg47Gln, Met113Val, Glu161Gly, Thr175Ala, Glu528Glyfs*6, Arg590Gln, Ala601Ser, Glu884Ter, Gly722Ala, Tyr775Met (x2), Trp854Ter...
September 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28902970/a-genetic-screen-in-rodent-malaria-parasites-identifies-five-new-apicoplast-putative-membrane-transporters-one-of-which-is-essential-in-human-malaria-parasites
#3
Claire P Sayers, Vanessa Mollard, Hayley D Buchanan, Geoffrey I McFadden, Christopher D Goodman
The malaria-causing parasite, Plasmodium, contains a unique non-photosynthetic plastid known as the apicoplast. The apicoplast is an essential organelle bound by four membranes. Although membrane transporters are attractive drug targets, only two transporters have been characterised in the malaria parasite apicoplast membranes. We selected 27 candidate apicoplast membrane proteins, 20 of which are annotated as putative membrane transporters, and performed a genetic screen in P. berghei to determine blood stage essentiality and subcellular localisation...
September 13, 2017: Cellular Microbiology
https://www.readbyqxmd.com/read/28894223/long-term-administration-of-nuclear-bile-acid-receptor-fxr-agonist-prevents-spontaneous-hepatocarcinogenesis-in-abcb4-mice
#4
Marica Cariello, Claudia Peres, Roberta Zerlotin, Emanuele Porru, Carlo Sabbà, Aldo Roda, Antonio Moschetta
Altered bile acid (BA) signaling is associated with hepatotoxicity. The farnesoid X receptor (FXR) is a nuclear receptor that transcriptionally regulates BA homeostasis. Mice with FXR ablation present hepatocarcinoma (HCC) due to high toxic BA levels. Mice with Abcb4 ablation accumulate toxic BA within the bile ducts and present HCC. We have previously shown that intestinal specific activation of FXR by transgenic VP16-FXR chimera is able to reduce BA pool size and prevent HCC. Here we tested chemical FXR activation by administering for 15 months the dual FXR/ membrane G protein-coupled receptor (TGR5) agonist INT-767 (6α-ethyl-3α,7α,23-trihydroxy-24-nor-5β-cholan-23-sulphate) to Fxr(-/-) and Abcb4(-/-) mice...
September 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28881789/pulmonary-endothelial-cell-dna-methylation-signature-in-pulmonary-arterial-hypertension
#5
Aurélie Hautefort, Julie Chesné, Jens Preussner, Soni S Pullamsetti, Jorg Tost, Mario Looso, Fabrice Antigny, Barbara Girerd, Marianne Riou, Saadia Eddahibi, Jean-François Deleuze, Werner Seeger, Elie Fadel, Gerald Simonneau, David Montani, Marc Humbert, Frédéric Perros
Pulmonary arterial hypertension (PAH) is a severe and incurable pulmonary vascular disease. One of the primary origins of PAH is pulmonary endothelial dysfunction leading to vasoconstriction, aberrant angiogenesis and smooth muscle cell proliferation, endothelial-to-mesenchymal transition, thrombosis and inflammation. Our objective was to study the epigenetic variations in pulmonary endothelial cells (PEC) through a specific pattern of DNA methylation. DNA was extracted from cultured PEC from idiopathic PAH (n = 11), heritable PAH (n = 10) and controls (n = 18)...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881751/hepatitis-b-virus-surface-proteins-accelerate-cholestatic-injury-and-tumor-progression-in-abcb4-knockout-mice
#6
Daniel Zahner, Hannah Glimm, Tomomitsu Matono, Yuri Churin, Diran Herebian, Ertan Mayatepek, Kernt Köhler, Stefan Gattenlöhner, Anne Stinn, Annette Tschuschner, Martin Roderfeld, Elke Roeb
Understanding of the pathophysiology of cholestasis associated carcinogenesis could challenge the development of new personalized therapeutic approaches and thus improve prognosis. Simultaneous damage might aggravate hepatic injury, induce chronic liver disease and even promote carcinogenesis. We aimed to study the effect of Hepatitis B virus surface protein (HBsAg) on cholestatic liver disease and associated carcinogenesis in a mouse model combining both impairments. Hybrids of Abcb4(-/-) and HBsAg transgenic mice were bred on fibrosis susceptible background BALB/c...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28777859/-delineating-a-case-with-a-complex-karyotype-by-using-combined-genetic-techniques
#7
Ning Han, Lu Kuang, Bing Zhu, Liang Hua, Wanling Li
OBJECTIVE: To explore the pathogenesis of a child with growth retardation, liver damage and congenital heart disease. METHODS: G-banded chromosomal karyotyping, high-throughput next-generation sequencing (HT-NGS)and fluorescence in situ hybridization(FISH) were used to characterize the structural chromosomal aberration. RESULTS: The child was found to have a karyotype of 46, XX, t(1;2) (q25;q21), t(7;20) (q21;p13). HT-NGS has detected a microdeletion at 2q21...
August 10, 2017: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
https://www.readbyqxmd.com/read/28757171/genetic-determinants-of-cholangiopathies-molecular-and-systems-genetics
#8
REVIEW
Matthias C Reichert, Rabea A Hall, Marcin Krawczyk, Frank Lammert
Familial cholangiopathies are rare but potentially severe diseases. Their spectrum ranges from fairly benign conditions as, for example, benign recurrent intrahepatic cholestasis to low-phospholipid associated cholelithiasis and progressive familial intrahepatic cholestasis (PFIC). Many cholangiopathies such as primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) affect first the bile ducts ("ascending pathophysiology") but others, such as PFIC, start upstream in hepatocytes and cause progressive damage "descending" down the biliary tree and leading to end-stage liver disease...
July 27, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28733223/sequencing-of-fic1-bsep-and-mdr3-in-a-large-cohort-of-patients-with-cholestasis-revealed-a-high-number-of-different-genetic-variants
#9
Carola Dröge, Michele Bonus, Ulrich Baumann, Caroline Klindt, Elke Lainka, Simone Kathemann, Florian Brinkert, Enke Grabhorn, Eva-Doreen Pfister, Daniel Wenning, Alexander Fichtner, Daniel N Gotthardt, Karl Heinz Weiss, Patrick McKiernan, Ratna Dua Puri, I C Verma, Stefanie Kluge, Holger Gohlke, Lutz Schmitt, Ralf Kubitz, Dieter Häussinger, Verena Keitel
BACKGROUND & AIMS: The bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4) and the ATPase familial intrahepatic cholestasis 1 (FIC1, ATP8B1) mediate bile formation. This study aimed to determine the contribution of mutations and common variants in the FIC1, BSEP and MDR3 genes to cholestatic disorders of differing disease onset and severity. METHODS: Coding exons with flanking intron regions of ATP8B1, ABCB11, and ABCB4 were sequenced in cholestatic patients with assumed genetic cause...
December 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28692147/persisting-hyperbilirubinemia-in-patients-with-paroxysmal-nocturnal-hemoglobinuria-pnh-chronically-treated-with-eculizumab-the-role-of-hepatocanalicular-transporter-variants
#10
Ferras Alashkar, Susanne N Weber, Colin Vance, Dörte Herich-Terhürne, Ulrich Dührsen, Frank Lammert, Alexander Röth
BACKGROUND: Eculizumab-treated paroxysmal nocturnal hemoglobinuria (PNH) patients (pts) show a dramatic decrease in serum lactate dehydrogenase (LDH) activities and bilirubin concentrations. However, some pts remain hyperbilirubinemic, possibly indicating an inadequate response due to extravascular hemolysis. METHODS: Mutation analyses of hepatocanalicular transporter/nuclear receptor variants (ABCB4, ABCB11, ATP8B1, NR1H4) were performed in eight (five of eight males; mean age 38 years [range 26-68 years]) out of the 174 pts with PNH/-clone at our department due to a persistent increase in total bilirubin concentrations (median 3...
July 10, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28624525/regulation-of-hepatic-abcb4-and-cyp3a65-gene-expression-and-multidrug-multixenobiotic-resistance-mdr-mxr-functional-activity-in-the-model-teleost-danio-rerio-zebrafish
#11
Jeremy S Jackson, Christopher J Kennedy
Multidrug/multixenobiotic resistance (MDR/MXR) confers resistance to a diverse range of potentially toxic pharmaceuticals and environmental contaminants through a cellular response that involves the coordinated induction and activity of the ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) and the Phase I metabolizing enzyme cytochrome P450 3A (CYP3A). In mammals, ligand-mediated pregnane X receptor (PXR) transcriptional activity regulates the induction of P-gp and CYP3A; however, this mechanism has not been well-characterized in piscine species...
June 15, 2017: Comparative Biochemistry and Physiology. Toxicology & Pharmacology: CBP
https://www.readbyqxmd.com/read/28617446/cathepsin-l-and-b-as-potential-markers-for-liver-fibrosis-insights-from-patients-and-experimental-models
#12
Mansi Manchanda, Prasenjit Das, Gaurav P S Gahlot, Ratnakar Singh, Elke Roeb, Martin Roderfeld, Siddhartha Datta Gupta, Anoop Saraya, R M Pandey, Shyam S Chauhan
OBJECTIVES: Cathepsin L (CTSL) and B (CTSB) have a crucial role in extracellular matrix (ECM) degradation and tissue remodeling, which is a prominent feature of fibrogenesis. The aim of this study was to determine the role and clinical significance of these cathepsins in liver fibrosis. METHODS: Hepatic histological CTSL and CTSB expression were assessed in experimental models of liver fibrosis, patients with liver cirrhosis, chronic viral hepatitis, and controls by real-time PCR and immunohistochemistry...
June 15, 2017: Clinical and Translational Gastroenterology
https://www.readbyqxmd.com/read/28617195/light-and-clock-control-of-genes-involved-in-detoxification
#13
G Carmona-Antoñanzas, M Santi, H Migaud, L M Vera
Circadian regulation of hepatic detoxification seems to be amongst the key roles of the biological clock. The liver is the major site for biotransformation, and in mammals, it contains several clock-controlled transcription factors such as proline and acidic amino acid-rich basic leucine zipper proteins (PAR bZIP) and basic-helix-loop-helix Per-Arnt-Sim (bHLH-PAS) family that act as circadian regulators of detoxification genes. This investigation explored the existence of daily and circadian expression of transcription factors involved in detoxification, as well as the temporal profile of a set of their target genes in zebrafish liver...
2017: Chronobiology International
https://www.readbyqxmd.com/read/28611303/tumor-suppressive-effect-of-s-adenosylmethionine-supplementation-in-a-murine-model-of-inflammation-mediated-hepatocarcinogenesis-is-dependent-on-treatment-longevity
#14
Evgeniy Stoyanov, Lina Mizrahi, Devorah Olam, Temima Schnitzer-Perlman, Eithan Galun, Daniel S Goldenberg
Chronic inflammation precedes the majority of hepatocellular carcinoma (HCC) cases. We investigated the chemopreventive potential of S-adenosylmethionine (SAM), an essential donor for all methylation reactions in the cell, at the late precancerous stage of HCC development using the Mdr2-knockout (Mdr2-KO, Abcb4-/-) mice, a model of inflammation-mediated hepatocarcinogenesis. Previously, we revealed down-regulation of the genes regulating SAM metabolism in the liver of these mice at the precancerous stages. Now, we have supplied Mdr2-KO mice at the late precancerous stage with SAM during either a short-term (17 days) or a long-term (51 days) period and explored the effects of such supplementation on tumor development, DNA methylation and gene expression in the liver...
May 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28611294/microarray-based-detection-and-expression-analysis-of-new-genes-associated-with-drug-resistance-in-ovarian-cancer-cell-lines
#15
Radosław Januchowski, Karolina Sterzyńska, Piotr Zawierucha, Marcin Ruciński, Monika Świerczewska, Małgorzata Partyka, Katarzyna Bednarek-Rajewska, Maciej Brązert, Michał Nowicki, Maciej Zabel, Andrzej Klejewski
PURPOSE: The present study is to discover a new genes associated with drug resistance development in ovarian cancer. METHODS: We used microarray analysis to determine alterations in the level of expression of genes in cisplatin- (CisPt), doxorubicin- (Dox), topotecan- (Top), and paclitaxel- (Pac) resistant variants of W1 and A2780 ovarian cancer cell lines. Immunohistochemistry assay was used to determine protein expression in ovarian cancer patients. RESULTS: We observed alterations in the expression of 22 genes that were common to all three cell lines that were resistant to the same cytostatic drug...
July 25, 2017: Oncotarget
https://www.readbyqxmd.com/read/28587926/comparison-of-in-silico-prediction-and-experimental-assessment-of-abcb4-variants-identified-in-patients-with-biliary-diseases
#16
Boudour Khabou, Anne-Marie Durand-Schneider, Jean-Louis Delaunay, Tounsia Aït-Slimane, Véronique Barbu, Faiza Fakhfakh, Chantal Housset, Michèle Maurice
Genetic variations of the phosphatidylcholine transporter, ABCB4 cause several biliary diseases. The large number of reported variations makes it difficult to foresee a comprehensive study of each variation. To appreciate the reliability of in silico prediction programs, 1) we confronted them with the assessment in cell models of two ABCB4 variations (E528D and P1161S) identified in patients with low phospholipid-associated cholelithiasis (LPAC); 2) we extended the confrontation to 19 variations that we had previously characterized in cellulo...
June 3, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28572541/pulmonary-endothelial-cell-dna-methylation-signature-in-pulmonary-arterial-hypertension
#17
Aurélie Hautefort, Julie Chesné, Jens Preussner, Soni S Pullamsetti, Jorg Tost, Mario Looso, Fabrice Antigny, Barbara Girerd, Marianne Riou, Saadia Eddahibi, Jean-François Deleuze, Werner Seeger, Elie Fadel, Gerald Simonneau, David Montani, Marc Humbert, Frédéric Perros
Pulmonary arterial hypertension (PAH) is a severe and incurable pulmonary vascular disease. One of the primary origins of PAH is pulmonary endothelial dysfunction leading to vasoconstriction, aberrant angiogenesis and smooth muscle cell proliferation, endothelial-to-mesenchymal transition, thrombosis and inflammation. Our objective was to study the epigenetic variations in pulmonary endothelial cells (PEC) through a specific pattern of DNA methylation.DNA was extracted from cultured PEC from idiopathic PAH (n = 11), heritable PAH (n = 10) and controls (n = 18)...
May 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/28497004/progressive-familial-intrahepatic-cholestasis-type-2-in-an-indian-child
#18
Ira Shah, Sujeet Chilkar
Progressive familial intrahepatic cholestasis (PFIC) is a chronic cholestasis syndrome that begins in infancy and usually progresses to cirrhosis within the first decade of life. There are three varieties of PFIC described: PFIC-1 occurs due to mutations in the ATP8B1 gene mapped to 18q21.31, PFIC-2 due to mutations in ABCB11 mapped to 2q24, and PFIC-3 due to mutations in ABCB4 located on 7q21.12. We report an Indian child whose mutation analysis was suggestive of PFIC-2. He underwent a biliary diversion at 3½ years of age but subsequently died secondary to massive hematemesis...
June 2017: Journal of Pediatric Genetics
https://www.readbyqxmd.com/read/28436434/phosphatidylethanolamine-dynamics-are-required-for-osteoclast-fusion
#19
Atsushi Irie, Kei Yamamoto, Yoshimi Miki, Makoto Murakami
Osteoclasts, responsible for bone resorption, are multinucleated cells formed by cell-cell fusion of mononuclear pre-osteoclasts. Although osteoclast fusion is a pivotal step for osteoclastogenesis, little is known about the mechanism involved. To clarify the underlying process, we investigated dynamics of membrane phospholipids during osteoclastogenesis in vitro. We found that the cellular content of phospholipids, phosphatidylethanolamine (PE) in particular, was increased during osteoclast differentiation...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28390947/expression-patterns-of-nuclear-receptors-in-parenchymal-and-non-parenchymal-mouse-liver-cells-and-their-modulation-in-cholestasis
#20
Ester Gonzalez-Sanchez, Delphine Firrincieli, Chantal Housset, Nicolas Chignard
Nuclear receptors (NR), the largest family of transcription factors, control many physiological and pathological processes. To gain insight into hepatic NR and their potential as therapeutic targets in cholestatis, we determined their expression in individual cell types of the mouse liver in normal and cholestatic conditions. Hepatocytes, cholangiocytes, hepatic stellate cells (HSC), sinusoidal endothelial cells (SEC) and Kupffer cells (KC) were isolated from the liver of mice with acute or chronic cholestasis (i...
April 6, 2017: Biochimica et Biophysica Acta
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