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https://www.readbyqxmd.com/read/28194423/effects-of-liver-fibrosis-progression-on-tissue-relaxation-times-in-different-mouse-models-assessed-by-ultrahigh-field-magnetic-resonance-imaging
#1
Andreas Müller, Katrin Hochrath, Jonas Stroeder, Kanishka Hittatiya, Günther Schneider, Frank Lammert, Arno Buecker, Peter Fries
Recently, clinical studies demonstrated that magnetic resonance relaxometry with determination of relaxation times T1 and T2(⁎) may aid in staging and management of liver fibrosis in patients suffering from viral hepatitis and steatohepatitis. In the present study we investigated T1 and T2(⁎) in different models of liver fibrosis to compare alternate pathophysiologies in their effects on relaxation times and to further develop noninvasive quantification methods of liver fibrosis. MRI was performed with a fast spin echo sequence for measurement of T1 and a multigradient echo sequence for determination of T2(⁎)...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28184004/ets-proto-oncogene-1-transcriptionally-up-regulates-the-cholangiocyte-senescence-associated-protein-cyclin-dependent-kinase-inhibitor-2a
#2
Steven P O'Hara, Patrick L Splinter, Christy E Trussoni, Maria J Lorenzo Pisarello, Lorena Loarca, Noah S Splinter, Bryce F Schutte, Nicholas F LaRusso
Primary sclerosing cholangitis (PSC) is a chronic, fibro-inflammatory cholangiopathy (disease of the bile ducts) of unknown pathogenesis. We reported that cholangiocyte senescence features prominently in PSC and neuroblastoma RAS viral oncogene homolog (NRAS) is activated in PSC cholangiocytes. Additionally, persistent microbial insult (e.g., lipopolysaccharides [LPS]) induces Cyclin Dependent Kinase Inhibitor 2A (CDKN2A/p16INK4a) expression and senescence in cultured cholangiocytes in an NRAS-dependent manner...
February 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28178654/hepatitis-b-virus-surface-proteins-accelerate-cholestatic-injury-and-tumor-progression-in-abcb4-knockout-mice
#3
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...
February 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28127842/hepatocarcinogenesis-in-multidrug-resistant-p-glycoprotein-3-deficiency
#4
Mukul Vij, Naresh P Shanmugam, Mettu Srinivas Reddy, Sanjay Govil, Mohamed Rela
MDR3 is a hepatocyte canalicular membrane protein encoded by the ABCB4 gene located on chromosome 7. MDR3 mediates the translocation of phosphatidylcholine into bile. Severe MDR 3 deficiency typically presents during early childhood with chronic cholestasis evolving to cirrhosis and portal hypertension, requiring liver transplantation. Herein, we report a case of severe MDR3 deficiency in a male child diagnosed with negative MDR3 immunostaining in hepatic canaliculi who underwent LDLT at our centre. We also describe single incidentally detected early well-differentiated HCC in the explant liver...
January 27, 2017: Pediatric Transplantation
https://www.readbyqxmd.com/read/28012258/functional-defect-of-variants-in-the-adenosine-triphosphate-binding-sites-of-abcb4-and-their-rescue-by-the-cystic-fibrosis-transmembrane-conductance-regulator-potentiator-ivacaftor-vx-770
#5
Jean-Louis Delaunay, Alix Bruneau, Brice Hoffmann, Anne-Marie Durand-Schneider, Véronique Barbu, Emmanuel Jacquemin, Michèle Maurice, Chantal Housset, Isabelle Callebaut, Tounsia Aït-Slimane
: ABCB4 (MDR3) is an adenosine triphosphate (ATP)-binding cassette (ABC) transporter expressed at the canalicular membrane of hepatocytes, where it mediates phosphatidylcholine (PC) secretion. Variations in the ABCB4 gene are responsible for several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), a rare disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of ABCB4 missense variations that reside in the highly conserved motifs of ABC transporters, involved in ATP binding...
February 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28010888/dose-dependent-effects-of-morphine-on-lipopolysaccharide-lps-induced-inflammation-and-involvement-of-multixenobiotic-resistance-mxr-transporters-in-lps-efflux-in-teleost-fish
#6
Hélène Mottaz, Rene Schönenberger, Stephan Fischer, Rik I L Eggen, Kristin Schirmer, Ksenia J Groh
Opioid drugs, such as morphine (MO), detected in aquatic environments worldwide, may harm fish due to their semi-persistence and ability to potently interact with molecular targets conserved across vertebrates. Here, we established a waterborne bacterial lipopolysaccharide (LPS) challenge assay with zebrafish embryos as a model to investigate chemically-induced disruption of the innate immune system, and used it to study the effects of MO exposure. Exposure to 1 mg/L MO resulted in pronounced immunosuppression, reflected in downregulation of several inflammation-related genes, including myd88, trif, traf6, p38, nfκb2, il-1β, il-8 and ccl34a...
February 2017: Environmental Pollution
https://www.readbyqxmd.com/read/27995969/biliary-phospholipids-sustain-enterocyte-proliferation-and-intestinal-tumor-progression-via-nuclear-receptor-lrh1-in-mice
#7
Michele Petruzzelli, Elena Piccinin, Claudio Pinto, Claudia Peres, Elena Bellafante, Antonio Moschetta
The proliferative-crypt compartment of the intestinal epithelium is enriched in phospholipids and accumulation of phospholipids has been described in colorectal tumors. Here we hypothesize that biliary phospholipid flow could directly contribute to the proliferative power of normal and dysplastic enterocytes. We used Abcb4(-/-) mice which lack biliary phospholipid secretion. We first show that Abcb4(-/-) mice are protected against intestinal tumorigenesis. At the molecular level, the transcriptional activity of the nuclear receptor Liver Receptor Homolog-1 (Lrh1) is reduced in Abcb4(-/-) mice and its re-activation re-establishes a tumor burden comparable to control mice...
December 20, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27939613/pharmacotoxicology-of-clinically-relevant-concentrations-of-obeticholic-acid-in-an-organotypic-human-hepatocyte-system
#8
A Dash, R A Figler, B R Blackman, S Marukian, M S Collado, M J Lawson, S A Hoang, A J Mackey, D Manka, B K Cole, R E Feaver, A J Sanyal, B R Wamhoff
Nonalcoholic steatohepatitis (NASH) is an emerging health crisis with no approved therapies. Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, shows promise in NASH trials. However, the precise mechanisms mediating OCA effects and impact on cholesterol metabolism are not fully understood. We explored the pharmaco-toxicological effects of OCA on patho-physiological pathways in hepatocytes using a previously described perfused organotypic liver system that allows culture in near-physiological insulin/glucose milieus, and exhibits drug responses at clinically-relevant concentrations...
March 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/27898169/cross-sectional-analysis-of-progressive-familial-intrahepatic-cholestasis-in-puerto-rican-children
#9
Dellys M Soler, Antonio I Del Valle, David Fernandez-Lube, Benjamin L Shneider
OBJECTIVE: Specific inherited disorders may be more common in island communities. Prior case reports suggest that cholestatic liver diseases may constitute a group of these inherited disorders in Puerto Rico. A cross-sectional survey of liver diseases in children was conducted to assess this hypothesis. METHODS: A cross-sectional analysis was performed in patients with chronic cholestasis at "Hospital Pediátrico Universitario" in San Juan, Puerto Rico. Ten potential participants with high gamma-glutamyl transpeptidase (GGTP) cholestasis were identified...
December 2016: Puerto Rico Health Sciences Journal
https://www.readbyqxmd.com/read/27895309/hepatocyte-specific-expression-of-an-oncogenic-variant-of-%C3%AE-catenin-results-in-cholestatic-liver-disease
#10
Ursula J Lemberger, Claudia 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...
November 23, 2016: Oncotarget
https://www.readbyqxmd.com/read/27883295/identification-of-novel-snps-associated-with-risk-and-prognosis-in-patients-with-castration-resistant-prostate-cancer
#11
Tristan M Sissung, John Deeken, Crystal R Leibrand, Douglas K Price, Sheryl Ehrlich, Seth M Steinberg, David J Liewehr, William Dahut, William D Figg
AIM: Metabolism and transport play major roles in life-long exposure to endogenous and exogenous carcinogens. We therefore explored associations between polymorphisms in absorption, distribution, metabolism and elimination genes and the risk and prognosis of castration-resistant prostate cancer (CRPC). MATERIALS & METHODS: A total of 634 genotypes were tested in 74 patients using the Affymetrix DMETv1.0 platform. RESULTS: No relation to risk was found...
December 2016: Pharmacogenomics
https://www.readbyqxmd.com/read/27825922/ursodeoxycholic-acid-therapy-in-intrahepatic-cholestasis-of-pregnancy-results-in-real-world-conditions-and-factors-predictive-of-response-to-treatment
#12
Yannick Bacq, Matthieu le Besco, Anne-Isabelle Lecuyer, Chantal Gendrot, Jérôme Potin, Christian R Andres, Alexandre Aubourg
BACKGROUND: Ursodeoxycholic acid (UDCA) therapy is commonly used in intrahepatic cholestasis of pregnancy (ICP). AIM: To evaluate the efficacy and tolerance of UDCA in real-world conditions and to search for factors predictive of response to treatment. METHODS: This observational study included 98 consecutive patients suffering from pruritus during pregnancy associated with increased ALT levels or total bile acid (TBA) concentrations, without other causes of cholestasis...
January 2017: Digestive and Liver Disease
https://www.readbyqxmd.com/read/27810576/effects-of-pharmaceuticals-and-personal-care-products-ppcps-on-multixenobiotic-resistance-mxr-related-efflux-transporter-activity-in-zebrafish-danio-rerio-embryos
#13
V Cunha, K Burkhardt-Medicke, P Wellner, M M Santos, P Moradas-Ferreira, T Luckenbach, M Ferreira
Certain ATP binding cassette (ABC) transporter proteins, such as zebrafish Abcb4, are efflux pumps acting as a cellular defence against a wide range of different, potentially toxic chemical compounds thus mediating so called multixenobiotic resistance (MXR). Certain chemicals target MXR proteins and, as so called chemosensitisers, inhibit the activity of these proteins thus increasing the toxicity of other chemicals that would normally be effluxed. In this study 14 pharmaceuticals and personal care products (PPCPs) that are being increasingly detected in aquatic systems, were assessed for interference with the MXR system of zebrafish (Danio rerio)...
February 2017: Ecotoxicology and Environmental Safety
https://www.readbyqxmd.com/read/27788395/in-silico-investigation-of-the-impact-of-synonymous-variants-in-abcb4-gene-on-mrna-stability-structure-splicing-accuracy-and-codon-usage-potential-contribution-to-pfic3-disease
#14
Boudour Khabou, Olfa Siala-Sahnoun, Lamia Gargouri, Emna Mkaouar-Rebai, Leila Keskes, Mongia Hachicha, Faiza Fakhfakh
Progressive Familial Intrahepatic Cholestasis type 3 (PFIC3) is an autosomal-recessive liver disease due to mutations in the ABCB4 gene encoding for the MDR3 protein. In the present study, we performed molecular and bioinformatic analyses in PFIC3 patients in order to understand the molecular basis of the disease. The three studied patients with PFIC3 were screened by PCR amplification followed by direct sequencing of the 27 coding exons of ABCB4. In silico analysis was performed by bioinformatic programs. We revealed three synonymous polymorphisms c...
October 22, 2016: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/27664577/characterization-of-acquired-paclitaxel-resistance-of-breast-cancer-cells-and-involvement-of-abc-transporters
#15
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/27513977/danio-rerio-embryos-on-prozac-effects-on-the-detoxification-mechanism-and-embryo-development
#16
V Cunha, P Rodrigues, M M Santos, P Moradas-Ferreira, M Ferreira
In the past decade the presence of psychopharmaceuticals, including fluoxetine (FLU), in the aquatic environment has been associated with the increasing trend in human consumption of these substances. Aquatic organisms are usually exposed to chronic low doses and, therefore, risk assessments should evaluate the effects of these compounds in non-target organisms. Teleost fish possess an array of active defence mechanisms to cope with the deleterious effects of xenobiotics. These include ABC transporters, phase I and II of cellular detoxification and oxidative stress enzymes...
September 2016: Aquatic Toxicology
https://www.readbyqxmd.com/read/27391331/tlr4-deficiency-protects-against-hepatic-fibrosis-and-diethylnitrosamine-induced-pre-carcinogenic-liver-injury-in-fibrotic-liver
#17
Susanne Nicole Weber, Annika Bohner, Dianne H Dapito, Robert F Schwabe, Frank Lammert
BACKGROUND: The development of hepatocellular carcinoma (HCC) is a common consequence of advanced liver fibrosis but the interactions between fibrogenesis and carcinogenesis are still poorly understood. Recently it has been shown that HCC promotion depends on Toll-like receptor (TLR) 4. Pre-cancerogenous events can be modelled in mice by the administration of a single dose of diethylnitrosamine (DEN), with HCC formation depending amongst others on interleukin (IL) 6 production. Mice lacking the hepatocanalicular phosphatidylcholine transporter ABCB4 develop liver fibrosis spontaneously, resemble patients with sclerosing cholangitis due to mutations of the orthologous human gene, and represent a valid model to study tumour formation in pre-injured cholestatic liver...
2016: PloS One
https://www.readbyqxmd.com/read/27277198/the-stepwise-evolution-of-the-exome-during-acquisition-of-docetaxel-resistance-in-breast-cancer-cells
#18
Stine Ninel Hansen, Natasja Spring Ehlers, Shida Zhu, Mathilde Borg Houlberg Thomsen, Rikke Linnemann Nielsen, Dongbing Liu, Guangbiao Wang, Yong Hou, Xiuqing Zhang, Xun Xu, Lars Bolund, Huanming Yang, Jun Wang, Jose Moreira, Henrik J Ditzel, Nils Brünner, Anne-Sofie Schrohl, Jan Stenvang, Ramneek Gupta
BACKGROUND: Resistance to taxane-based therapy in breast cancer patients is a major clinical problem that may be addressed through insight of the genomic alterations leading to taxane resistance in breast cancer cells. In the current study we used whole exome sequencing to discover somatic genomic alterations, evolving across evolutionary stages during the acquisition of docetaxel resistance in breast cancer cell lines. RESULTS: Two human breast cancer in vitro models (MCF-7 and MDA-MB-231) of the step-wise acquisition of docetaxel resistance were developed by exposing cells to 18 gradually increasing concentrations of docetaxel...
2016: BMC Genomics
https://www.readbyqxmd.com/read/27256251/functional-characterization-of-abcb4-mutations-found-in-progressive-familial-intrahepatic-cholestasis-type-3
#19
Hyo Jin Park, Tae Hee Kim, So Won Kim, Shin Hye Noh, Kyeong Jee Cho, Choe Choi, Eun Young Kwon, Yang Ji Choi, Heon Yung Gee, Ji Ha Choi
Multidrug resistance 3 (MDR3), encoded by the ATP-binding cassette, subfamily B, member 4 gene (ABCB4), localizes to the canalicular membrane of hepatocytes and translocates phosphatidylcholine from the inner leaflet to the outer leaflet of the canalicular membrane. Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare hepatic disease caused by genetic mutations of ABCB4. In this study, we characterized 8 ABCB4 mutations found in PFIC3 patients, using in vitro molecular assays. First, we examined the transport activity of each mutant by measuring its ATPase activity using paclitaxel or phosphatidylcholine...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27203216/down-regulation-of-abcg2-and-abcb4-transporters-in-the-placenta-of-rats-exposed-to-cadmium
#20
Lili Liu, Liang Zhou, Shuiwang Hu, Shanyu Zhou, Yingyu Deng, Ming Dong, Jianxun Huang, Yuli Zeng, Xiaoyan Chen, Na Zhao, Hongling Li, Zhenhua Ding
As a maternal and developmental toxicant, cadmium (Cd) possesses weak penetrability through the placental barrier. However, the underlying mechanism remains unclear. To gain insight into the protein molecules associated with Cd toxicity in placenta and explore their roles in Cd transportation, a reproductive animal experiment was carried out using Sprague-Dawley rats. We performed proteomic analysis of the placenta by Difference Gel Electrophoresis (DIGE) combined with Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Tandem Mass Spectroscopy (MALDI-TOF/TOF MS)...
June 21, 2016: Oncotarget
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