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Farnesoid x receptor

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https://www.readbyqxmd.com/read/28808886/assessment-of-pharmacokinetic-interactions-between-obeticholic-acid-and-caffeine-midazolam-warfarin-dextromethorphan-omeprazole-rosuvastatin-and-digoxin-in-phase-1-studies-in-healthy-subjects
#1
Jeffrey E Edwards, Lise Eliot, Andrew Parkinson, Sharon Karan, Leigh MacConell
INTRODUCTION: Obeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the potential drug-drug interaction effect of OCA on metabolic CYP450 enzymes and drug transporters. METHODS: Five phase 1 single-center, open-label, fixed-sequence, inpatient studies were conducted in healthy adult subjects to evaluate the effect of oral daily doses of 10 or 25 mg OCA on single-dose plasma pharmacokinetics of specific probe substrates for enzymes CYP1A2 (caffeine, R-warfarin), CYP3A (midazolam, R-warfarin), CYP2C9 (S-warfarin), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), and drug transporters, BCRP/OATP1B1/OATP1B3 (rosuvastatin), and P-gp (digoxin)...
August 14, 2017: Advances in Therapy
https://www.readbyqxmd.com/read/28805978/obeticholic-acid-a-selective-farnesoid-x-receptor-agonist-regulates-bile-acid-homeostasis-in-sandwich-cultured-human-hepatocytes
#2
Yuanyuan Zhang, Jonathan P Jackson, Robert L St Claire, Kimberly Freeman, Kenneth R Brouwer, Jeffrey E Edwards
Farnesoid X receptor (FXR) is a master regulator of bile acid homeostasis through transcriptional regulation of genes involved in bile acid synthesis and cellular membrane transport. Impairment of bile acid efflux due to cholangiopathies results in chronic cholestasis leading to abnormal elevation of intrahepatic and systemic bile acid levels. Obeticholic acid (OCA) is a potent and selective FXR agonist that is 100-fold more potent than the endogenous ligand chenodeoxycholic acid (CDCA). The effects of OCA on genes involved in bile acid homeostasis were investigated using sandwich-cultured human hepatocytes...
August 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28796169/cell-surface-and-nuclear-receptors-in-the-colon-as-targets-for-bacterial-metabolites-and-its-relevance-to-colon-health
#3
REVIEW
Sathish Sivaprakasam, Yangzom D Bhutia, Sabarish Ramachandran, Vadivel Ganapathy
The symbiotic co-habitation of bacteria in the host colon is mutually beneficial to both partners. While the host provides the place and food for the bacteria to colonize and live, the bacteria in turn help the host in energy and nutritional homeostasis, development and maturation of the mucosal immune system, and protection against inflammation and carcinogenesis. In this review, we highlight the molecular mediators of the effective communication between the bacteria and the host, focusing on selective metabolites from the bacteria that serve as messengers to the host by acting through selective receptors in the host colon...
August 10, 2017: Nutrients
https://www.readbyqxmd.com/read/28792854/phytosterols-synergize-with-endotoxin-to-augment-inflammation-in-kupffer-cells-but-alone-have-limited-direct-effect-on-hepatocytes
#4
Gregory Guthrie, Bryan Tackett, Barbara Stoll, Camilia Martin, Oluyinka Olutoye, Douglas G Burrin
INTRODUCTION: Phytosterols are implicated in the development of parenteral nutrition-associated liver disease. A newly proposed mechanism for phytosterol-mediated parenteral nutrition-associated liver disease is through phytosterol-facilitated hepatic proinflammatory cytokine release following exposure to intestinally derived bacteria. Whether the proinflammatory effects are liver cell specific is not known. AIM: To determine if phytosterols cause inflammation in hepatocytes or Kupffer cells independently or require costimulation by lipopolysaccharide (LPS)...
August 1, 2017: JPEN. Journal of Parenteral and Enteral Nutrition
https://www.readbyqxmd.com/read/28774887/suppressed-hepatic-bile-acid-signalling-despite-elevated-production-of-primary-and-secondary-bile-acids-in-nafld
#5
Na Jiao, Susan S Baker, Adrian Chapa-Rodriguez, Wensheng Liu, Colleen A Nugent, Maria Tsompana, Lucy Mastrandrea, Michael J Buck, Robert D Baker, Robert J Genco, Ruixin Zhu, Lixin Zhu
OBJECTIVE: Bile acids are regulators of lipid and glucose metabolism, and modulate inflammation in the liver and other tissues. Primary bile acids such as cholic acid and chenodeoxycholic acid (CDCA) are produced in the liver, and converted into secondary bile acids such as deoxycholic acid (DCA) and lithocholic acid by gut microbiota. Here we investigated the possible roles of bile acids in non-alcoholic fatty liver disease (NAFLD) pathogenesis and the impact of the gut microbiome on bile acid signalling in NAFLD...
August 3, 2017: Gut
https://www.readbyqxmd.com/read/28767077/gut-liver-axis-derangement-in-non-alcoholic-fatty-liver-disease
#6
REVIEW
Marco Poeta, Luca Pierri, Pietro Vajro
Non-alcoholic fatty liver disease (NAFLD) is the most frequent type of chronic liver disease in the pediatric age group, paralleling an obesity pandemic. A "multiple-hit" hypothesis has been invoked to explain its pathogenesis. The "first hit" is liver lipid accumulation in obese children with insulin resistance. In the absence of significant lifestyle modifications leading to weight loss and increased physical activity, other factors may act as "second hits" implicated in liver damage progression leading to more severe forms of inflammation and hepatic fibrosis...
August 2, 2017: Children
https://www.readbyqxmd.com/read/28766509/high-density-lipoprotein-metabolism-and-reverse-cholesterol-transport-strategies-for-raising-hdl-cholesterol
#7
Katerina Tosheska Trajkovska, Sonja Topuzovska
A key to effective treatment of cardiovascular disease is to understand the body's complex lipoprotein transport system. Reverse cholesterol transport (RCT) is the process of cholesterol movement from the extrahepatic tissues back to the liver. Lipoproteins containing apoA-I [highdensity lipoprotein (HDL)] are key mediators in RCT, whereas non-high-density lipoproteins (non-HDL, lipoproteins containing apoB) are involved in the lipid delivery pathway. HDL particles are heterogeneous; they differ in proportion of proteins and lipids, size, shape, and charge...
August 2017: Anatolian Journal of Cardiology
https://www.readbyqxmd.com/read/28766097/ranking-docking-poses-by-graph-matching-of-protein-ligand-interactions-lessons-learned-from-the-d3r-grand-challenge-2
#8
Priscila da Silva Figueiredo Celestino Gomes, Franck Da Silva, Guillaume Bret, Didier Rognan
A novel docking challenge has been set by the Drug Design Data Resource (D3R) in order to predict the pose and affinity ranking of a set of Farnesoid X receptor (FXR) agonists, prior to the public release of their bound X-ray structures and potencies. In a first phase, 36 agonists were docked to 26 Protein Data Bank (PDB) structures of the FXR receptor, and next rescored using the in-house developed GRIM method. GRIM aligns protein-ligand interaction patterns of docked poses to those of available PDB templates for the target protein, and rescore poses by a graph matching method...
August 1, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28762281/clinical-significance-of-farnesoid-x-receptor-expression-in-thyroid-neoplasia
#9
Constantinos Giaginis, Nikolaos Tsoukalas, Paraskevi Alexandrou, Gerasimos Tsourouflis, Eugene Dana, Ioanna Delladetsima, Efstratios Patsouris, Stamatios Theocharis
AIM: To evaluate the clinical significance of farnesoid X receptor (FXR) in thyroid neoplasia. PATIENTS & METHODS: FXR expression was assessed immunohistochemically on 88 thyroid neoplastic tissues (benign = 44, malignant = 44). RESULTS: Enhanced FXR was more frequently observed in papillary carcinomas compared with hyperplastic nodules (p = 0.0489). In malignant lesions, elevated FXR was associated with capsular (p = 0.0004) and vascular invasion (p = 0...
August 1, 2017: Future Oncology
https://www.readbyqxmd.com/read/28749691/nonacidic-farnesoid-x-receptor-modulators
#10
Daniel Flesch, Sun-Yee Cheung, Jurema Schmidt, Matthias Gabler, Pascal Heitel, Jan Kramer, Astrid Kaiser, Markus Hartmann, Mara Lindner, Kerstin Lüddens-Dämgen, Jan Heering, Christina Lamers, Hartmut Lüddens, Mario Wurglics, Ewgenij Proschak, Manfred Schubert-Zsilavecz, Daniel Merk
As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. Clinical results have validated FXR as therapeutic target in hepatic and metabolic diseases. To date, potent FXR agonists share a negatively ionizable function that might compromise their pharmacokinetic distribution and behavior. Here we report the development and characterization of a high-affinity FXR modulator not comprising an acidic residue.
August 8, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28746779/hepatic-farnesoid-x-receptor-protein-level-and-circulating-fibroblast-growth-factor-19-concentration-in-children-with-nafld
#11
Valerio Nobili, Anna Alisi, Antonella Mosca, Claudia Della Corte, Silvio Veraldi, Rita De Vito, Cristiano De Stefanis, Valentina D'Oria, Joerg Jahnel, Evelyn Zohrer, Eleonora Scorletti, Christopher D Byrne
BACKGROUND & AIMS: Treatment with the farnesoid X receptor (FXR) agonist obeticholic acid is ineffective in some patients with non-alcoholic steatohepatitis (NASH) but the explanation is uncertain. We investigated hepatic FXR expression, and measurements of fibroblast growth factor 19 (FGF19) and bile acids (BAs) in children with NAFLD to investigate relationships with NASH. METHODS: 33 children with NAFLD who underwent diagnostic liver biopsy were studied. Hepatic FXR protein levels and circulating FGF19 concentrations were compared with those analyzed in five control subjects with proven normal liver histology...
July 26, 2017: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/28739572/altenusin-a-non-steroidal-microbial-metabolite-attenuates-non-alcoholic-fatty-liver-disease-by-activating-the-farnesoid-x-receptor
#12
Zhihui Zheng, Zanmei Zhao, Shuqiang Li, Xinhua Lu, Mengxi Jiang, Jie Lin, Yunqi An, Yang Xie, Meishu Xu, Wenbin Shen, Grace Guo, YIxian Huang, Song Li, Xuexia Zhang, Wen Xie
Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease. The incidence of NAFLD has increased steadily due to its close association with the global epidemic of obesity and type 2 diabetes. However, there is no effective pharmacological therapy approved for NAFLD. Farnesoid X receptor (FXR), a member of the nuclear receptor subfamily, plays important roles in maintaining the homeostasis of bile acids, glucose and lipids. FXR agonists have shown promise for the treatment of NAFLD. Here we report Altenusin (2076A), a natural non-steroidal fungal metabolite, as a novel selective agonist of FXR with an EC50 value of 3...
July 24, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28729691/lowered-fasting-chenodeoxycholic-acid-correlated-with-the-decrease-of-fibroblast-growth-factor-19-in-chinese-subjects-with-impaired-fasting-glucose
#13
Jing Zhang, Huating Li, Hu Zhou, Li Fang, Jingjing Xu, Han Yan, Shuqin Chen, Qianqian Song, Yinan Zhang, Aimin Xu, Qichen Fang, Yang Ye, Weiping Jia
The gut-derived hormone Fibroblast growth factor 19 (FGF19) could regulate glucose metabolism and is induced by bile acids (BAs) through activating Farnesoid X Receptor (FXR). FGF19 was found to decrease in subjects with isolated-impaired fasting glucose (I-IFG) and type 2 diabetes mellitus (T2DM). However, the reason for the change of FGF19 in subjects with different glucometabolic status remained unclear. Here we measured six BAs including chenodeoxycholic acid (CDCA), cholic acid, deoxycholic acid, their glycine conjugates and FGF19 levels during oral glucose tolerance test (OGTT) in normal glucose tolerance (NGT), isolated-impaired glucose tolerance, I-IFG, combined glucose intolerance (CGI) and T2DM subjects...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28714273/%C3%AE-catenin-regulation-of-farnesoid-x-receptor-signaling-and-bile-acid-metabolism-during-murine-cholestasis
#14
Michael D Thompson, Akshata Moghe, Pamela Cornuet, Rebecca Marino, Jianmin Tian, Pengcheng Wang, Xiaochao Ma, Marc Abrams, Joseph Locker, Satdarshan P S Monga, Kari Nejak-Bowen
Cholestatic liver diseases result from impaired bile flow and are characterized by inflammation, atypical ductular proliferation (ADP), and fibrosis. The Wnt/β-catenin pathway plays a role in bile duct development, yet its role in cholestatic injury remains indeterminate. Liver-specific β-catenin knockout (KO) mice and wild-type (WT) littermates were subjected to cholestatic injury via bile duct ligation or short-term exposure to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Intriguingly, KO exhibit a dramatic protection from liver injury, fibrosis, and ADP, which coincided with significantly decreased total hepatic bile acids (BA)...
July 17, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28711154/western-diet-induced-dysbiosis-in-farnesoid-x-receptor-knockout-mice-causes-persistent-hepatic-inflammation-after-antibiotic-treatment
#15
Prasant K Jena, Lili Sheng, Hui-Xin Liu, Karen M Kalanetra, Annie Mirsoian, William J Murphy, Samuel W French, Viswanathan V Krishnan, David A Mills, Yu-Jui Yvonne Wan
Patients who have liver cirrhosis and liver cancer also have reduced farnesoid X receptor (FXR). The current study analyzes the effect of diet through microbiota that affect hepatic inflammation in FXR knockout (KO) mice. Wild-type and FXR KO mice were on a control (CD) or Western diet (WD) for 10 months. In addition, both CD- and WD-fed FXR KO male mice, which had hepatic lymphocyte and neutrophil infiltration, were treated by vancomycin, polymyxin B, and Abx (ampicillin, neomycin, metronidazole, and vancomycin)...
August 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28709961/bile-acids-fgf15-19-and-liver-regeneration-from-mechanisms-to-clinical-applications
#16
REVIEW
Gloria Alvarez-Sola, Iker Uriarte, Maria U Latasa, Maddalen Jimenez, Marina Barcena-Varela, Eva Santamaría, Raquel Urtasun, Carlos Rodriguez-Ortigosa, Jesús Prieto, Pedro Berraondo, Maite G Fernandez-Barrena, Carmen Berasain, Matías A Avila
The liver has an extraordinary regenerative capacity rapidly triggered upon injury or resection. This response is intrinsically adjusted in its initiation and termination, a property termed the "hepatostat". Several molecules have been involved in liver regeneration, and among them bile acids may play a central role. Intrahepatic levels of bile acids rapidly increase after resection. Through the activation of farnesoid X receptor (FXR), bile acids regulate their hepatic metabolism and also promote hepatocellular proliferation...
July 11, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28704214/bile-acids-upregulate-brca1-and-downregulate-estrogen-receptor-1-gene-expression-in-ovarian-cancer-cells
#17
Qunyan Jin, Olivier Noel, Mai Nguyen, Lionel Sam, Glenn S Gerhard
Two major risk factors for ovarian cancer include loss-of-function mutations in the BRCA1 (breast cancer 1, early onset) gene and aspects of estrogen metabolism. Modulation of the levels of the normal BRCA1 allele and estrogen receptor expression may therefore be a preventive strategy. Consensus binding motifs for the bile acid-responsive transcription factor farnesoid X receptor were identified in the BRCA1 and estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2) genes, supported by chromatin immunoprecipitation sequencing data...
July 12, 2017: European Journal of Cancer Prevention
https://www.readbyqxmd.com/read/28702667/microengineered-cultures-containing-human-hepatic-stellate-cells-and-hepatocytes-for-drug-development
#18
Matthew D Davidson, David A Kukla, Salman R Khetani
In non-alcoholic steatohepatitis (NASH), hepatic stellate cells (HSC) differentiate into myofibroblast-like cells that cause fibrosis, which predisposes patients to cirrhosis and hepatocellular carcinoma. Thus, modeling interactions between activated HSCs and hepatocytes in vitro can aid in the development of anti-NASH/fibrosis therapeutics and lead to a better understanding of disease progression. Species-specific differences in drug metabolism and disease pathways now necessitate the supplementation of animal studies with data acquired using human liver models; however, current models do not adequately model the negative effects of primary human activated HSCs on the phenotype of otherwise well-differentiated primary human hepatocytes (PHHs) as in vivo...
August 14, 2017: Integrative Biology: Quantitative Biosciences From Nano to Macro
https://www.readbyqxmd.com/read/28696246/farnesoid-x-receptor-agonism-protects-against-diabetic-tubulopathy-potential-add-on-therapy-for-diabetic-nephropathy
#19
Andi Marquardt, Moh'd Mohanad Al-Dabet, Sanchita Ghosh, Shrey Kohli, Jayakumar Manoharan, Ahmed ElWakiel, Ihsan Gadi, Fabian Bock, Sumra Nazir, Hongjie Wang, Jonathan A Lindquist, Peter Paul Nawroth, Thati Madhusudhan, Peter R Mertens, Khurrum Shahzad, Berend Isermann
Established therapies for diabetic nephropathy (dNP) delay but do not prevent its progression. The shortage of established therapies may reflect the inability to target the tubular compartment. The chemical chaperone tauroursodeoxycholic acid (TUDCA) ameliorates maladaptive endoplasmic reticulum (ER) stress signaling and experimental dNP. Additionally, TUDCA activates the farnesoid X receptor (FXR), which is highly expressed in tubular cells. We hypothesized that TUDCA ameliorates maladaptive ER signaling via FXR agonism specifically in tubular cells...
July 10, 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28669602/the-bile-acid-nuclear-receptor-fxr%C3%AE-is-a-critical-regulator-of-mouse-germ-cell-fate
#20
Emmanuelle Martinot, Lauriane Sèdes, Marine Baptissart, Hélène Holota, Betty Rouaisnel, Christelle Damon-Soubeyrand, Angélique De Haze, Jean-Paul Saru, Christelle Thibault-Carpentier, Céline Keime, Jean-Marc A Lobaccaro, Silvère Baron, Gérard Benoit, Françoise Caira, Claude Beaudoin, David H Volle
Spermatogenesis is the process by which spermatozoa are generated from spermatogonia. This cell population is heterogeneous, with self-renewing spermatogonial stem cells (SSCs) and progenitor spermatogonia that will continue on a path of differentiation. Only SSCs have the ability to regenerate and sustain spermatogenesis. This makes the testis a good model to investigate stem cell biology. The Farnesoid X Receptor alpha (FXRα) was recently shown to be expressed in the testis. However, its global impact on germ cell homeostasis has not yet been studied...
July 11, 2017: Stem Cell Reports
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