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https://www.readbyqxmd.com/read/29330220/regulation-of-drug-metabolism-by-the-interplay-of-inflammatory-signaling-steatosis-and-xeno-sensing-receptors-in-heparg-cells
#1
Norman Tanner, Lisa Kubik, Claudia Luckert, Maria Thomas, Ute Hofmann, Ulrich M Zanger, Linda Bohmert, Alfonso Lampen, Albert Braeuning
Non-alcoholic fatty liver disease (NAFLD), characterized by triglyceride deposition in hepatocytes due to imbalanced lipid homeostasis, is of increasing concern in Western countries, with progression to non-alcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. Previous studies suggest a complex, mutual influence of hepatic fat accumulation, NASH-related inflammatory mediators, and drug-sensing receptors regulating xenobiotic metabolism. Here, we investigated the suitability of human HepaRG hepatocarcinoma cells as a model for NAFLD and NASH...
January 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29301936/mapping-two-neurosteroid-modulatory-sites-in-the-prototypic-pentameric-ligand-gated-ion-channel-glic
#2
Wayland W L Cheng, Zi-Wei Chen, John R Bracamontes, Melissa M Budelier, Kathiresan Krishnan, Daniel J Shin, Cunde Wang, Xin Jiang, Douglas F Covey, Gustav Akk, Alex S Evers
Neurosteroids are endogenous sterols that potentiate or inhibit pentameric ligand gated ion channels (pLGICs), and can be effective anesthetics, analgesics, or anti-epileptic drugs. The complex effects of neurosteroids on pLGICs suggest the presence of multiple binding sites in these receptors. Here, using a series of novel neurosteroid photolabeling reagents combined with top-down and middle-down mass spectrometry, we have determined the stoichiometry, sites and orientation of binding for 3α,5α-pregnane neurosteroids in the Gloeobacter ligand gated ion channel (GLIC), a prototypic pLGIC,...
January 4, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29286073/proteasome-inhibition-protects-against-diet-induced-gallstone-formation-through-modulation-of-cholesterol-and-bile-acid-homeostasis
#3
Eun-Ji Lee, Min Hee Kim, Ye-Ryung Kim, Joo-Won Park, Woo-Jae Park
Gallstone disease is one of the most prevalent and costly gastrointestinal disorders worldwide. Gallstones are formed in the biliary system by cholesterol secretions in bile, which result from excess cholesterol, a deficiency in bile salts or a combination of the two. The present study examined the effects of proteasome inhibition on gallstone formation using the proteasome inhibitors bortezomib (BT) and carfilzomib (CF). C57BL/6J mice were fed a lithogenic diet to generate gallstones and injected with BT or CF for 12 weeks...
December 15, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/29277707/the-in-vitro-metabolism-of-11%C3%AE-hydroxyprogesterone-and-11-ketoprogesterone-to-11-ketodihydrotestosterone-in-the-backdoor-pathway
#4
Desmaré van Rooyen, Rachelle Gent, Lise Barnard, Amanda C Swart
Increased circulating 11β-hydroxyprogesterone (11OHP4), biosynthesised in the human adrenal, is associated with 21-hydroxylase deficiency in congenital adrenal hyperplasia. 17α-hydroxyprogesterone levels are also increased, with the steroid's metabolism to dihydrotestosterone in the backdoor pathway contributing to hyperandrogenic clinical conditions. In this study we investigated the in vitro biosynthesis and downstream metabolism of 11OHP4. Both cytochrome P450 11β-hydroxylase and aldosterone synthase catalyse the biosynthesis of 11OHP4 from progesterone (P4) which is converted to 11-ketoprogesterone (11KP4) by 11β-hydroxysteroid dehydrogenase type 2, while type 1 readily catalysed the reverse reaction...
December 23, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29247817/generation-of-a-pxr-reporter-human-induced-pluripotent-stem-cell-line-pxr-mcherry-hipsc-using-the-crispr-cas9-system
#5
Hyemin Kim, Ji-Woo Kim, So-Jin Kim, Young-Jun Choi, Dae-Sung Kim, Han-Jin Park
Pregnane X receptor (PXR) is a key nuclear receptor that mediates drug metabolism and stimulates hepatocyte proliferation. However, the lack of PXR expression in human pluripotent stem cell-derived hepatocytes limits their application for drug screening and toxicity testing. Here, we generated a PXR-mCherry reporter human induced pluripotent stem cell (hiPSC) line using the CRISPR/Cas9 system. PXR-mCherry hiPSCs were pluripotent and had differentiation potential and a normal karyotype. This cell line is an important tool for identifying factors that increase PXR-mediated drug metabolism and hepatocyte proliferation...
December 6, 2017: Stem Cell Research
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
#6
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
#7
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/29222744/activation-of-intestinal-gr-fxr-and-ppar%C3%AE-ugt-signaling-exacerbates-ibuprofen-induced-enteropathy-in-mice
#8
Zhiqiang Lu, Yuanfu Lu, Xue Wang, Fangyu Wang, Youcai Zhang
Nonsteroidal anti-inflammatory drugs (NSAIDs)-induced small intestinal injury (enteropathy) occurs in about two-thirds of regular NSAID users. To date, there is no proven-effective treatment for NSAID enteropathy, and its underlying mechanism remains obscure. The present study showed that glucocorticoids are an important determinant of NSAID enteropathy. High dose dexamethasone (DEX, 75 mg/kg) markedly exacerbated the acute toxicity of ibuprofen (IBU, 200 mg/kg) in the small intestine of mice, which was not due to the pregnane-X-receptor pathway...
December 8, 2017: Archives of Toxicology
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
#9
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
#10
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
#11
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
#12
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/29184608/role-of-pregnane-x-receptor-in-regulating-bacterial-translocation-in-chronic-liver-diseases
#13
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
#14
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/29177473/skeletal-muscle-interleukin-6-regulates-hepatic-cytochrome-p450-expression-effects-of-16-weeks-high-fat-diet-and-exercise
#15
Jakob G Knudsen, Lærke Bertholdt, Anders Gudiksen, Sabine Gerbal-Chaloin, Martin Krøyer Rasmussen
High fat diet (HFD) induce several changes to the pathways regulating energy homeostasis and changes the expression of the hepatic cytochrome p450 (Cyp) enzyme-system. Despite these pervious findings, it is still unclear how the effects of HFD and especially HFD in combination with treadmill running affect hepatic Cyp expression. In the present study, we investigated the mRNA and protein expression of selected Cyp's in mice subjected to 16 weeks of HFD and treadmill running. To understand the regulatory mechanisms behind the exercise-induced reversion of the HFD induced changes in Cyp expression, we used a model in which the exercise induced myokine and known regulator of hepatic Cyp's, interleukin-6 (IL-6), was knocked out specifically in skeletal muscle...
November 21, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
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
#16
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/29158009/effect-of-carbamazepine-on-expression-of-udp-glucuronosyltransferase-1a6-and-1a7-in-rat-brain
#17
Yuki Asai, Yukiko Sakakibara, Masayuki Nadai, Miki Katoh
Because UDP-glucuronosyltransferase (Ugt) 1a6 and Ugt1a7 are highly expressed in the rat brain, changes in Ugt1a6 and Ugt1a7 expression may affect the pharmacokinetics of drugs and endogenous compounds in the brain. The present study aimed to elucidate the effect of carbamazepine (CBZ), a typical UGT inducer, on Ugt1a6 and Ugt1a7 expression in the rat brain. Sprague-Dawley rats were treated intraperitoneally for 7 d with CBZ (100 mg/kg/d). Ugt1a6 and Ugt1a7 mRNAs were induced by CBZ in the cerebellum, piriform cortex, and hippocampus (Ugt1a6: 3...
October 5, 2017: Drug Metabolism and Pharmacokinetics
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
#18
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
#19
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/29126514/structural-and-functional-evidences-for-the-interactions-between-nuclear-hormone-receptors-and-endocrine-disruptors-at-low-doses
#20
Patrick Balaguer, Vanessa Delfosse, Marina Grimaldi, William Bourguet
Endocrine-disrupting chemicals (EDCs) represent a broad class of exogenous substances that cause adverse effects in the endocrine system mainly by interacting with nuclear hormone receptors (NRs). Humans are generally exposed to low doses of pollutants, and current researches aim at deciphering the mechanisms accounting for the health impact of EDCs at environmental concentrations. Our correlative analysis of structural, interaction and cell-based data has revealed a variety of, sometimes unexpected, binding modes, reflecting a wide range of EDC affinities and specificities...
September 2017: Comptes Rendus Biologies
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