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https://www.readbyqxmd.com/read/29234281/interleukin-6-induces-dec1-promotes-dec1-interaction-with-rxr%C3%AE-and-suppresses-the-expression-of-pxr-car-and-their-target-genes
#1
Rui Ning, Yunran Zhan, Shuangcheng He, Jinhua Hu, Zhu Zhu, Gang Hu, Bingfang Yan, Jian Yang, Wei Liu
Inflammatory burden is a primary cellular event in many liver diseases, and the overall capacity of drug elimination is decreased. PXR (pregnane X receptor) and CAR (constitutive androstane receptor) are two master regulators of genes encoding drug-metabolizing enzymes and transporters. DEC1 (differentiated embryonic chondrocyte-expressed gene 1) is a ligand-independent transcription factor and reportedly is induced by many inflammatory cytokines including IL-6. In this study, we used primary hepatocytes (human and mouse) as well as HepG2 cell line and demonstrated that IL-6 increased DEC1 expression and decreased the expressions of PXR, CAR, and their target genes...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29233651/identification-of-bicyclic-hexafluoroisopropyl-alcohol-sulfonamides-as-retinoic-acid-receptor-related-orphan-receptor-gamma-ror%C3%AE-rorc-inverse-agonists-employing-structure-based-drug-design-to-improve-pregnane-x-receptor-pxr-selectivity
#2
Hua Gong, David S Weinstein, Zhonghui Lu, James J-W Duan, Sylwia Stachura, Lauren Haque, Ananta Karmakar, Hemalatha Hemagiri, Dhanya Kumar Raut, Arun Kumar Gupta, Javed Khan, Dan Camac, John S Sack, Andrew Pudzianowski, Dauh-Rurng Wu, Melissa Yarde, Ding-Ren Shen, Virna Borowski, Jenny H Xie, Huadong Sun, Celia D'Arienzo, Marta Dabros, Michael A Galella, Faye Wang, Carolyn A Weigelt, Qihong Zhao, William Foster, John E Somerville, Luisa M Salter-Cid, Joel C Barrish, Percy H Carter, T G Murali Dhar
We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies...
December 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29219065/transactivation-assays-that-identify-indirect-and-direct-activators-of-human-pregnane-x-receptor-pxr-nr1i2-and-constitutive-androstane-receptor-car-nr1i3
#3
Marija Pinne, Elsa Ponce, Judy L Raucy
BACKGROUND: Nuclear receptors (NRs), including PXR and CAR, are presumed to be ligand-dependent transcription factors, but ligand binding is not an absolute requirement for activation. Indeed, many compounds activate PXR and CAR by indirect mechanisms. Detecting these indirect activators of specific nuclear receptors in vitro has been difficult. As NR activation of either or both PXR and CAR can lead to drug-drug interactions and adverse drug effects, false negatives obtained with screening tools incapable of detecting indirect activators could present liabilities...
December 6, 2017: Drug Metabolism Letters
https://www.readbyqxmd.com/read/29212764/aberrant-dna-methylation-of-pregnane-x-receptor-underlies-metabolic-gene-alterations-in-the-diabetic-kidney
#4
Atsushi Watanabe, Takeshi Marumo, Wakako Kawarazaki, Mitsuhiro Nishimoto, Nobuhiro Ayuzawa, Kohei Ueda, Daigoro Hirohama, Toshiya Tanaka, Shintaro Yagi, Satoshi Ota, Genta Nagae, Hiroyuki Aburatani, Hiroo Kumagai, Toshiro Fujita
Epigenetic abnormalities have been suggested to mediate metabolic memory observed in diabetic complications. We have shown that epigenetic alterations may induce persistent phenotypic changes in the proximal tubules of the diabetic kidneys. In this study, we show that pregnane X receptor (PXR), a xenobiotic nuclear receptor, is epigenetically altered and upregulated, and may have a possible function in the diabetic kidney. PXR has been shown to play a critical role in metabolic changes in obesity and diabetes; however, its distribution and function in the kidney are unknown...
December 6, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/29209109/resveratrol-modifies-biliary-secretion-of-cholephilic-compounds-in-sham-operated-and-cholestatic-rats
#5
Eva Dolezelova, Alena Prasnicka, Jolana Cermanova, Alejandro Carazo, Lucie Hyrsova, Milos Hroch, Jaroslav Mokry, Michaela Adamcova, Alena Mrkvicova, Petr Pavek, Stanislav Micuda
AIM: To investigate the effect of resveratrol on biliary secretion of cholephilic compounds in healthy and bile duct-obstructed rats. METHODS: Resveratrol (RSV) or saline were administered to rats by daily oral gavage for 28 d after sham operation or reversible bile duct obstruction (BDO). Bile was collected 24 h after the last gavage during an intravenous bolus dose of the Mdr1/Mrp2 substrate azithromycin. Bile acids, glutathione and azithromycin were measured in bile to quantify their level of biliary secretion...
November 21, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29204052/pregnane-x-receptor-and-constitutive-androstane-receptor-modulate-differently-cyp3a-mediated-metabolism-in-early-and-late-stage-cholestasis
#6
Daniela Gabbia, Arianna Dalla Pozza, Laura Albertoni, Roberta Lazzari, Giorgia Zigiotto, Maria Carrara, Vincenzo Baldo, Tatjana Baldovin, Annarosa Floreani, Sara De Martin
AIM: To ascertain whether cholestasis affects the expression of two CYP3A isoforms (CYP3A1 and CYP3A2) and of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). METHODS: Cholestasis was induced by bile duct ligation in 16 male Wistar rats; whereas 8 sham-operated rats were used as controls. Severity of cholestasis was assessed on histological examination of liver sections, and serum concentrations of albumin, AST, ALT, GGT, ALPK and bilirubin...
November 14, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/29199543/genetic-variations-of-the-xenoreceptors-nr1i2-and-nr1i3-and-their-effect-on-drug-disposition-and-response-variability
#7
Litaty Céphanoée Mbatchi, Jean-Paul Brouillet, Alexandre Evrard
NR1I2 (PXR) and NR1I3 (CAR) are nuclear receptors that are classified as xenoreceptors. Upon activation by various xenobiotics, including marketed drugs, they regulate the transcription level of major drug-metabolizing enzymes and transporters and facilitate the elimination of xenobiotics from the body. The modulation of the activity of these two xenoreceptors by various ligands is a major source of pharmacokinetic variability of environmental origin. NR1I2 and NR1I3 genetic polymorphisms can affect the pharmacokinetics and therapeutic response to many drugs, such as irinotecan, tacrolimus and atazanavir...
December 4, 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/29184608/role-of-pregnane-x-receptor-in-regulating-bacterial-translocation-in-chronic-liver-diseases
#8
REVIEW
Sundhar Mohandas, Balasubramaniyan Vairappan
Bacterial translocation (BT) has been impeccably implicated as a driving factor in the pathogenesis of a spectrum of chronic liver diseases (CLD). Scientific evidence accumulated over the last four decades has implied that the disease pathologies in CLD and BT are connected as a loop in the gut-liver axis and exacerbate each other. Pregnane X receptor (PXR) is a ligand-activated transcription factor and nuclear receptor that is expressed ubiquitously along the gut-liver-axis. PXR has been intricately associated with the regulation of various mechanisms attributed in causing BT...
November 18, 2017: World Journal of Hepatology
https://www.readbyqxmd.com/read/29184146/2-3-4-5-tetrahydroxystilbene-2-o-%C3%AE-d-glucoside-exacerbates-acetaminophen-induced-hepatotoxicity-by-inducing-hepatic-expression-of-cyp2e1-cyp3a4-and-cyp1a2
#9
Shangfu Xu, Jie Liu, Jingshan Shi, Zhengtao Wang, Lili Ji
Hepatotoxicity induced by medicinal herb Polygonum multiflorum Thunb. attracts wide attention in the world recently. 2,3,4',5-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is a main active compound in Polygonum multiflorum Thunb. This study aims to observe TSG-provided the aggravation on acetaminophen (APAP)-induced hepatotoxicity in mice by inducing hepatic expression of cytochrome P450 (CYP450) enzymes. Serum alanine/aspartate aminotransferase (ALT/AST) analysis and liver histological evaluation showed that TSG (200, 400, 800 mg/kg) exacerbated the hepatotoxicity induced by sub-toxic dose of APAP (200 mg/kg) in mice, but TSG alone had no hepatotoxicity...
November 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29168799/modulation-of-cytochrome-p450-p-glycoprotein-and-pregnane-x-receptor-by-selected-antimalarial-herbs-implication-for-herb-drug-interaction
#10
Pius S Fasinu, Vamshi K Manda, Olivia R Dale, Nosa O Egiebor, Larry A Walker, Shabana I Khan
Seven medicinal plants popularly used for treating malaria in West Africa were selected to assess herb-drug interaction potential through a series of in vitro methods. Fluorescent cytochrome P450 (CYP) assays were conducted using the recombinant CYP enzymes for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 to assess the effect of the methanolic extracts on the metabolic activity of CYPs. Secondly, the inhibitory effect of the extracts was evaluated on P-glycoproteins (P-gp) using calcein-AM, a fluorescent substrate, in MDCK-II and hMDR1-MDCK-II cells...
November 23, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29157826/modulation-of-pregnane-x-receptor-pxr-and-constitutive-androstane-receptor-car-activation-by-ursolic-acid-ua-attenuates-rifampin-isoniazid-cytotoxicity
#11
Hsiao-Yun Chang, Chao-Jung Chen, Wei-Chih Ma, Wai-Kok Cheng, Yen-Ning Lin, Ying-Ray Lee, Jih-Jung Chen, Yun-Ping Lim
BACKGROUND: Interactions between transcriptional inducers of cytochrome P450 (CYP450) enzymes and therapeutic drugs may be prevented by antagonizing the activation of a nuclear receptor (NR), pregnane X receptor (PXR, NR1I2), thus improving therapeutic efficacy. PURPOSE: In the present study, we aim to identify that ursolic acid (UA), a widely distributed pentacyclic triterpene, may act as an effective antagonist of PXR and its sister NR receptor, constitutive androstane receptor (CAR, NR1I3)...
December 1, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/29145837/molecular-network-based-analysis-of-the-mechanism-of-liver-injury-induced-by-volatile-oils-from-artemisiae-argyi-folium
#12
Hongjie Liu, Sha Zhan, Yan Zhang, Yan Ma, Liang Chen, Lingxiu Chen, Hanqiu Dong, Min Ma, Zhe Zhang
BACKGROUND: Volatile oils from Artemisiae argyi folium (VOAAF) is reported with hepatotoxicity, but the underlying mechanism is still unclear. METHODS: In the present study this molecular mechanism was explored with the Ingenuity Pathway Analysis (IPA). The chemical components of the VOAAF were searched in the database, and their target proteins were all identified in the PubChem, while drug-induced liver injury (DILI) genes were searched in the PubMed gene databases...
November 16, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/29134945/drug-drug-interaction-potential-of-the-hepatitis-b-and-hepatitis-d-virus-entry-inhibitor-myrcludex-b-assessed-in-vitro
#13
Antje Blank, Katrin Meier, Stephan Urban, Walter Emil Haefeli, Johanna Weiss
BACKGROUND: Myrcludex B is a first-in-class virus entry inhibitor for patients with chronic hepatitis B or B/D infections. In patients it will be co-administered with drugs needed for the disease or comorbidities. We aimed to define the risk of drug-drug interactions by characterizing the influence of myrcludex B on relevant drug transporting and metabolizing enzymes in vitro. METHODS: Inhibition of P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP/ABCG2), and the organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1/SLCO1B1 and OATP1B3/SLCO1B3) was measured in cells over-expressing the respective transporter using fluorogenic substrates...
November 14, 2017: Antiviral Therapy
https://www.readbyqxmd.com/read/29133885/a-conserved-stem-of-the-myxococcus-xanthus-srna-pxr-controls-srna-accumulation-and-multicellular-development
#14
Yuen-Tsu N Yu, Elizabeth Cooper, Gregory J Velicer
The small RNA (sRNA) Pxr negatively controls multicellular fruiting body formation in the bacterium Myxococcus xanthus, inhibiting the transition from growth to development when nutrients are abundant. Like many other prokaryotic sRNAs, Pxr is predicted to fold into three stem loops (SL1-SL3). SL1 and SL2 are highly conserved across the myxobacteria, whereas SL3 is much more variable. SL1 is necessary for the regulatory function of Pxr but the importance of SL3 in this regard is unknown. To test for cis genetic elements required for Pxr function, we deleted the entire pxr gene from a developmentally defective strain that fails to remove Pxr-mediated blockage of development and reintroduced variably truncated fragments of the pxr region to test for their ability to block development...
November 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29126478/optimization-of-gc-tof-ms-analysis-conditions-for-assessing-host-gut-microbiota-metabolic-interactions-chinese-rhubarb-alters-fecal-aromatic-amino-acids-and-phenol-metabolism
#15
Shan Yin, Pan Guo, Dafu Hai, Li Xu, Jiale Shu, Wenjin Zhang, Muhammad Idrees Khan, Irwin J Kurland, Yunping Qiu, Yumin Liu
In this paper, an optimized method based on gas chromatography/time-of-flight mass spectrometry (GC-TOFMS) platform has been developed for the analysis of gut microbial-host related co-metabolites in fecal samples. The optimization was performed with proportion of chloroform (C), methanol (M) and water (W) for the extraction of specific metabolic pathways of interest. Loading Bi-plots from the PLS regression model revealed that high concentration of chloroform emphasized the extraction of short chain fatty acids and TCA intermediates, while the higher concentration of methanol emphasized indole and phenyl derivatives...
December 1, 2017: Analytica Chimica Acta
https://www.readbyqxmd.com/read/29125184/hepatic-and-hippocampal-cytochrome-p450-enzyme-overexpression-during-spontaneous-recurrent-seizures
#16
Leonie Runtz, Benoit Girard, Marion Toussenot, Julie Espallergues, Alexis Fayd'Herbe De Maudave, Alexandre Milman, Frederic deBock, Chaitali Ghosh, Nathalie C Guérineau, Jean-Marc Pascussi, Federica Bertaso, Nicola Marchi
OBJECTIVE: Available evidence points to a role of cytochrome P450 (Cyp) drug biotransformation enzymes in central nervous system diseases, including epilepsy. Deviations in drug pharmacokinetic profiles may impact therapeutic outcomes. Here, we ask whether spontaneous recurrent seizure (SRS) activity is sufficient to modulate the expression of major Cyp enzymes in the liver and brain. METHODS: Unilateral intrahippocampal (IH) kainic acid (KA) injections were used to elicit nonconvulsive status epilepticus (SE), epileptogenesis, and SRS, as monitored by video-electroencephalography...
November 10, 2017: Epilepsia
https://www.readbyqxmd.com/read/29124635/atropisomers-of-2-2-3-3-6-6-hexachlorobiphenyl-pcb-136-exhibit-stereoselective-effects-on-activation-of-nuclear-receptors-in-vitro
#17
Kateřina Pěnčíková, Petra Brenerová, Lucie Svržková, Eva Hrubá, Lenka Pálková, Jan Vondráček, Hans-Joachim Lehmler, Miroslav Machala
PCB 136 is an environmentally relevant chiral PCB congener, which has been found in vivo to be present in form of rotational isomers (atropisomers). Its atropselective biotransformation or neurotoxic effects linked with sensitization of ryanodine receptor suggest that it might interact also with other intracellular receptors in a stereospecific manner. However, possible atropselective effects of PCB 136 on nuclear receptor transactivation remain unknown. Therefore, in this study, atropselective effects of PCB 136 on nuclear receptors controlling endocrine signaling and/or expression of xenobiotic and steroid hormone catabolism were investigated...
November 9, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/29123032/pregnane-x-receptor-promotes-ethanol-induced-hepatosteatosis-in-mice
#18
Sora Choi, Prince Neequaye, Samuel W French, Frank J Gonzalez, Maxwell A Gyamfi
The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that modulates the metabolic response to drugs and toxic agents. Both PXR activation and deficiency promote hepatic triglyceride accumulation, a hallmark feature of alcoholic liver disease (ALD). However, the molecular mechanism of PXR-mediated activation of ethanol (EtOH)-induced steatosis is unclear. Here, using male wild type (WT) and Pxr-null mice we examined PXR-mediated regulation of chronic EtOH-induced hepatic lipid accumulation and hepatotoxicity...
November 9, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29119010/epigenetic-impact-of-endocrine-disrupting-chemicals-on-lipid-homeostasis-and-atherosclerosis-a-pregnane-x-receptor-centric-view
#19
Robert N Helsley, Changcheng Zhou
Despite the major advances in developing diagnostic techniques and effective treatments, atherosclerotic cardiovascular disease (CVD) is still the leading cause of mortality and morbidity worldwide. While considerable progress has been achieved to identify gene variations and environmental factors that contribute to CVD, much less is known about the role of "gene-environment interactions" in predisposing individuals to CVD. Our chemical environment has significantly changed in the last few decades, and there are more than 100,000 synthetic chemicals in the market...
October 1, 2017: Environmental Epigenetics
https://www.readbyqxmd.com/read/29117101/hepatotoxicity-of-herbal-supplements-mediated-by-modulation-of-cytochrome-p450
#20
REVIEW
Christopher Trent Brewer, Taosheng Chen
Herbal supplements are a significant source of drug-drug interactions (DDIs), herb-drug interactions, and hepatotoxicity. Cytochrome P450 (CYP450) enzymes metabolize a large number of FDA-approved pharmaceuticals and herbal supplements. This metabolism of pharmaceuticals and supplements can be augmented by concomitant use of either pharmaceuticals or supplements. The xenobiotic receptors constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) can respond to xenobiotics by increasing the expression of a large number of genes that are involved in the metabolism of xenobiotics, including CYP450s...
November 8, 2017: International Journal of Molecular Sciences
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