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Farnesoid x receptor

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https://www.readbyqxmd.com/read/28913782/docking-of-small-molecules-to-farnesoid-x-receptors-using-autodock-vina-with-the-convex-pl-potential-lessons-learned-from-d3r-grand-challenge-2
#1
Maria Kadukova, Sergei Grudinin
The 2016 D3R Grand Challenge 2 provided an opportunity to test multiple protein-ligand docking protocols on a set of ligands bound to farnesoid X receptor that has many available experimental structures. We participated in the Stage 1 of the Challenge devoted to the docking pose predictions, with the mean RMSD value of our submission poses of 2.9 Å. Here we present a thorough analysis of our docking predictions made with AutoDock Vina and the Convex-PL rescoring potential by reproducing our submission protocol and running a series of additional molecular docking experiments...
September 14, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28913743/predicting-the-affinity-of-farnesoid-x-receptor-ligands-through-a-hierarchical-ranking-protocol-a-d3r-grand-challenge-2-case-study
#2
Manon Réau, Florent Langenfeld, Jean-François Zagury, Matthieu Montes
The Drug Design Data Resource (D3R) Grand Challenges are blind contests organized to assess the state-of-the-art methods accuracy in predicting binding modes and relative binding free energies of experimentally validated ligands for a given target. The second stage of the D3R Grand Challenge 2 (GC2) was focused on ranking 102 compounds according to their predicted affinity for Farnesoid X Receptor. In this task, our workflow was ranked 5th out of the 77 submissions in the structure-based category. Our strategy consisted in (1) a combination of molecular docking using AutoDock 4...
September 14, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28912067/farnesoid-x-receptor-regulates-sult1e1-expression-through-inhibition-of-pgc1%C3%AE-binding-to-hnf4%C3%AE
#3
Shuai Wang, Xue Yuan, Danyi Lu, Lianxia Guo, Baojian Wu
Sulfotransferase 1E1 (SULT1E1, also known as estrogen sulfotransferase) plays an important role in metabolism and detoxification of many endogenous and exogenous compounds (e.g., estrogens and flavonoids). Here we aimed to assess the effects of farnesoid X receptor (FXR) activation on SULT1E1 expression, and to determine the mechanism thereof. Treatment with specific FXR agonists (i.e., GW4064 and CDCA) significantly decreased both mRNA and protein levels of SULT1E1 in HepG2 cells. This was accompanied by a decrease in the enzymatic activity...
September 11, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28910310/gugulipid-causes-hypercholesterolemia-leading-to-endothelial-dysfunction-increased-atherosclerosis-and-premature-death-by-ischemic-heart-disease-in-male-mice
#4
Andrea Leiva, Susana Contreras-Duarte, Ludwig Amigo, Esteban Sepúlveda, Mauricio Boric, Verónica Quiñones, Dolores Busso, Attilio Rigotti
For proper cholesterol metabolism, normal expression and function of scavenger receptor class B type I (SR-BI), a high-density lipoprotein (HDL) receptor, is required. Among the factors that regulate overall cholesterol homeostasis and HDL metabolism, the nuclear farnesoid X receptor plays an important role. Guggulsterone, a bioactive compound present in the natural product gugulipid, is an antagonist of this receptor. This natural product is widely used globally as a natural lipid-lowering agent, although its anti-atherogenic cardiovascular benefit in animal models or humans is unknown...
2017: PloS One
https://www.readbyqxmd.com/read/28910295/identification-of-a-mouse-lactobacillus-johnsonii-strain-with-deconjugase-activity-against-the-fxr-antagonist-t-%C3%AE-mca
#5
Michael DiMarzio, Brigida Rusconi, Neela H Yennawar, Mark Eppinger, Andrew D Patterson, Edward G Dudley
Bile salt hydrolase (BSH) activity against the bile acid tauro-beta-muricholic acid (T-β-MCA) was recently reported to mediate host bile acid, glucose, and lipid homeostasis via the farnesoid X receptor (FXR) signaling pathway. An earlier study correlated decreased Lactobacillus abundance in the cecum with increased concentrations of intestinal T-β-MCA, an FXR antagonist. While several studies have characterized BSHs in lactobacilli, deconjugation of T-β-MCA remains poorly characterized among members of this genus, and therefore it was unclear what strain(s) were responsible for this activity...
2017: PloS One
https://www.readbyqxmd.com/read/28900792/relative-binding-affinity-prediction-of-farnesoid-x-receptor-in-the-d3r-grand-challenge-2-using-fep
#6
Christina Schindler, Friedrich Rippmann, Daniel Kuhn
Physics-based free energy simulations have increasingly become an important tool for predicting binding affinity and the recent introduction of automated protocols has also paved the way towards a more widespread use in the pharmaceutical industry. The D3R 2016 Grand Challenge 2 provided an opportunity to blindly test the commercial free energy calculation protocol FEP+ and assess its performance relative to other affinity prediction methods. The present D3R free energy prediction challenge was built around two experimental data sets involving inhibitors of farnesoid X receptor (FXR) which is a promising anticancer drug target...
September 12, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28895119/fxr-controls-chop-expression-in-steatohepatitis
#7
Claudia D Fuchs, Thierry Claudel, Hubert Scharnagl, Tatjana Stojakovic, Michael Trauner
The farnesoid X receptor (FXR) and C/EBP homologous protein (CHOP) have critical functions in hepatic lipid metabolism. Here, we aimed to explore a potential relationship between FXR and CHOP. We fed wild-type (WT) and FXR KO mice a MCD-diet (model of steatohepatitis) and found that Chop mRNA expression is upregulated in WT but not FXR KO mice. Absence of FXR aggravates hepatic inflammation after MCD feeding. In HepG2 cells, we found that Chop expression is regulated in a FXR/Retinoid X receptor (RXR)-dependent manner...
September 12, 2017: FEBS Letters
https://www.readbyqxmd.com/read/28894223/long-term-administration-of-nuclear-bile-acid-receptor-fxr-agonist-prevents-spontaneous-hepatocarcinogenesis-in-abcb4-mice
#8
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/28892150/hepatic-inflammation-caused-by-dysregulated-bile-acid-synthesis-is-reversible-by-butyrate-supplementation
#9
Lili Sheng, Prasant Kumar Jena, Ying Hu, Hui-Xin Liu, Nidhi Nagar, Karen M Kalanetra, Samuel William French, Samuel Wheeler French, David A Mills, Yu-Jui Yvonne Wan
Dysregulated bile acid (BA) synthesis or reduced farnesoid x receptor (FXR) levels are found in patients having metabolic diseases, autoimmune hepatitis, and liver cirrhosis or cancer. The objective of this study was to establish the relationship between butyrate and dysregulated BA synthesis-induced hepatitis as well as the effect of butyrate in reversing the liver pathology. Wild type (WT) and FXR knockout (KO) male mice were placed on control (CD) or Western diet (WD) for 15 months. In the presence or absence of butyrate supplementation, feces obtained from 15-month-old WD-fed FXR KO mice, which had severe hepatitis and liver tumors, were transplanted to 7-month-old WD-fed FXR KO for 3 months...
September 11, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/28891815/rna-binding-protein-zfp36l1-maintains-posttranscriptional-regulation-of-bile-acid-metabolism
#10
Elizabeth J Tarling, Bethan L Clifford, Joan Cheng, Pauline Morand, Angela Cheng, Ellen Lester, Tamer Sallam, Martin Turner, Thomas Q de Aguiar Vallim
Bile acids function not only as detergents that facilitate lipid absorption but also as signaling molecules that activate the nuclear receptor farnesoid X receptor (FXR). FXR agonists are currently being evaluated as therapeutic agents for a number of hepatic diseases due to their lipid-lowering and antiinflammatory properties. FXR is also essential for maintaining bile acid homeostasis and prevents the accumulation of bile acids. Elevated bile acids activate FXR, which in turn switches off bile acid synthesis by reducing the mRNA levels of bile acid synthesis genes, including cholesterol 7α-hydroxylase (Cyp7a1)...
September 11, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28889350/binding-free-energy-predictions-of-farnesoid-x-receptor-fxr-agonists-using-a-linear-interaction-energy-lie-approach-with-reliability-estimation-application-to-the-d3r-grand-challenge-2
#11
Eko Aditya Rifai, Marc van Dijk, Nico P E Vermeulen, Daan P Geerke
Computational protein binding affinity prediction can play an important role in drug research but performing efficient and accurate binding free energy calculations is still challenging. In the context of phase 2 of the Drug Design Data Resource (D3R) Grand Challenge 2 we used our automated eTOX ALLIES approach to apply the (iterative) linear interaction energy (LIE) method and we evaluated its performance in predicting binding affinities for farnesoid X receptor (FXR) agonists. Efficiency was obtained by our pre-calibrated LIE models and molecular dynamics (MD) simulations at the nanosecond scale, while predictive accuracy was obtained for a small subset of compounds...
September 9, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28888833/iron-depletion-induces-hepatic-secretion-of-biliary-lipids-and-glutathione-in-rats
#12
Alena Prasnicka, Jolana Cermanova, Milos Hroch, Eva Dolezelova, Lucie Rozkydalova, Tomas Smutny, Alejandro Carazo, Jaroslav Chladek, Martin Lenicek, Petr Nachtigal, Libor Vitek, Petr Pavek, Stanislav Micuda
Iron depletion (ID) has been shown to induce the liver expression of Cyp7a1, the rate-limiting enzyme initiating conversion of cholesterol to bile acids (BA), although the effect on bile acids metabolism and bile production is unknown. Therefore, we investigated changes in bile secretion and BA synthesis during diet-induced iron depletion (ID) in rats. ID increased bile flow along with augmented biliary excretion of bile acids, glutathione, cholesterol and phospholipids. Accordingly, we found transcriptional upregulation of the Cyp7a1, Cyp8b1, and Cyp27a1 BA synthetic enzymes, as well as induction of the Abcg5/8 cholesterol transporters in ID rat livers...
September 6, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28887089/steviol-an-aglycone-of-steviol-glycoside-sweeteners-interacts-with-the-pregnane-x-pxr-and-aryl-hydrocarbon-ahr-receptors-in-detoxification-regulation
#13
Jan Dusek, Alejandro Carazo, Frantisek Trejtnar, Lucie Hyrsova, Ondřej Holas, Tomas Smutny, Stanislav Micuda, Petr Pavek
Stevia rebaudiana Bertoni is a herb known for the high content of natural sweeteners in its leaves. Its main secondary metabolite stevioside is used as non-caloric sweetener. No information, however, is available on whether stevioside or steviol interact with drug-metabolizing enzymes and pose the potential risk of food-drug interactions. Similarly, data are lacking on the interactions of steviol and stevioside with key nuclear receptors controlling the expression of the main drug metabolizing enzymes. We studied the interactions of steviol and stevioside with the pregnane X (PXR), vitamin D (VDR), constitutive androstane (CAR), farnesoid X (FXR), glucocorticoid (GR) and aryl hydrocarbon (AHR) receptors, which control expression of genes of xenobiotic metabolism...
September 5, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28884249/cdocker-and-formula-see-text-dynamics-for-prospective-prediction-in-d3r-grand-challenge-2
#14
Xinqiang Ding, Ryan L Hayes, Jonah Z Vilseck, Murchtricia K Charles, Charles L Brooks
The opportunity to prospectively predict ligand bound poses and free energies of binding to the Farnesoid X Receptor in the D3R Grand Challenge 2 provided a useful exercise to evaluate CHARMM based docking (CDOCKER) and [Formula: see text]-dynamics methodologies for use in "real-world" applications in computer aided drug design. In addition to measuring their current performance, several recent methodological developments have been analyzed retrospectively to highlight best procedural practices in future applications...
September 7, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28879536/binding-affinities-of-the-farnesoid-x-receptor-in-the-d3r-grand-challenge-2-estimated-by-free-energy-perturbation-and-docking
#15
Martin A Olsson, Alfonso T García-Sosa, Ulf Ryde
We have studied the binding of 102 ligands to the farnesoid X receptor within the D3R Grand Challenge 2016 blind-prediction competition. First, we employed docking with five different docking software and scoring functions. The selected docked poses gave an average root-mean-squared deviation of 4.2 Å. Consensus scoring gave decent results with a Kendall's τ of 0.26 ± 0.06 and a Spearman's ρ of 0.41 ± 0.08. For a subset of 33 ligands, we calculated relative binding free energies with free-energy perturbation...
September 6, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28873070/functional-assessment-of-genetic-variants-located-in-the-promoter-of-shp1-nr0b2
#16
Katharina Prestin, Maria Olbert, Janine Hussner, Henry Völzke, Henriette E Meyer Zu Schwabedissen
Small heterodimer partner 1 (SHP1, NR0B2) is a member of the superfamily of nuclear receptors (NRs). Even if this orphan receptor, unlike other NRs, lacks the DNA-binding domain, it is capable of regulating transcription by repressing the activity of other NRs by direct protein-protein interaction. Accordingly, SHP1 is part of negative feedback loops of the transcriptional regulation of genes involved in drug metabolism and various metabolic pathways including bile acid and glucose homeostasis. Although it is known that several interacting partners of SHP1 also modulate its expression, there is little information about genetic variability of this regulatory mechanism...
August 31, 2017: Pharmacogenetics and Genomics
https://www.readbyqxmd.com/read/28865056/blinded-evaluation-of-farnesoid-x-receptor-fxr-ligands-binding-using-molecular-docking-and-free-energy-calculations
#17
Edithe Selwa, Eddy Elisée, Agustin Zavala, Bogdan I Iorga
Our participation to the D3R Grand Challenge 2 involved a protocol in two steps, with an initial analysis of the available structural data from the PDB allowing the selection of the most appropriate combination of docking software and scoring function. Subsequent docking calculations showed that the pose prediction can be carried out with a certain precision, but this is dependent on the specific nature of the ligands. The correct ranking of docking poses is still a problem and cannot be successful in the absence of good pose predictions...
September 2, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28856736/interactions-between-bile-salts-gut-microbiota-and-hepatic-innate-immunity
#18
REVIEW
Kristin Schubert, Steven W M Olde Damink, Martin von Bergen, Frank G Schaap
Bile salts are the water-soluble end products of hepatic cholesterol catabolism that are released into the duodenum and solubilize lipids due to their amphipathic structure. Bile salts also act as endogenous ligands for dedicated nuclear receptors that exert a plethora of biological processes, mostly related to metabolism. Bile salts are actively reclaimed in the distal part of the small intestine, released into the portal system, and subsequently extracted by the liver. This enterohepatic cycle is critically dependent on dedicated bile salt transporters...
September 2017: Immunological Reviews
https://www.readbyqxmd.com/read/28854753/proteomic-identification-of-turkey-meleagris-gallopavo-seminal-plasma-proteins
#19
M Slowinska, J Nynca, G J Arnold, T Fröhlich, J Jankowski, K Kozlowski, A Mostek, A Ciereszko
SDS-PAGE combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and 2-dimensional electrophoresis (2DE) combined with matrix-assisted laser desorption/ionization time of flight/time of flight mass spectrometry (MALDI TOF/TOF) were applied to characterize the turkey seminal plasma proteome. LC-MS/MS led to the identification of 175 proteins, which were classified according to their function and to corresponding biochemical pathways. Using 2DE and MALDI TOF/TOF, 34 different turkey seminal plasma proteins could be identified, of which 20 were found in more than one spot, indicating different proteoforms of these proteins...
September 1, 2017: Poultry Science
https://www.readbyqxmd.com/read/28852062/farnesoid-x-receptor-activation-protects-the-kidney-from-ischemia-reperfusion-damage
#20
Zhibo Gai, Lei Chu, Zhenqiang Xu, Xiaoming Song, Dongfeng Sun, Gerd A Kullak-Ublick
Farnesoid X receptor (FXR) activation has been reported to reduce inflammation and oxidative stress. Because both inflammation and oxidative stress are critical for tissue destruction during kidney ischemia reperfusion (I/R) injury, we investigated the protective role of FXR against kidney damage induced by I/R in mice. Mice undergoing renal I/R developed the typical features of acute kidney injury (AKI): increased creatinine, albuminuria, tubular necrosis and apoptosis. Inflammatory cytokine production and oxidative stress were also markedly increased...
August 29, 2017: Scientific Reports
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