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https://www.readbyqxmd.com/read/28938455/bile-acid-alterations-are-associated-with-insulin-resistance-but-not-with-nash-in-obese-subjects
#1
Vanessa Legry, Sven Francque, Joel T Haas, An Verrijken, Sandrine Caron, Oscar Chávez-Talavera, Emmanuelle Vallez, Luisa Vonghia, Eveline Dirinck, Ann Verhaegen, Mostafa Kouach, Sophie Lestavel, Philippe Lefebvre, Luc Van Gaal, Anne Tailleux, Réjane Paumelle, Bart Staels
Context: Bile acids (BA) are signalling molecules controlling energy homeostasis which can be both toxic and protective for the liver. BA alterations have been reported in obesity, insulin resistance (IR) and non-alcoholic steatohepatitis (NASH). However whether BA alterations contribute to NASH independently of the metabolic status is unclear. Objective: To assess BA alterations associated with NASH independently of BMI and IR. Design & Setting: Patients visiting the obesity clinic of the Antwerp University Hospital (a tertiary referral facility) were recruited from 2006 to 2014...
August 4, 2017: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/28927887/epidermal-overexpression-of-xenobiotic-receptor-pxr-impairs-the-epidermal-barrier-and-triggers-th2-immune-response
#2
Andreas Elentner, Matthias Schmuth, Nikolaos Yannoutsos, Thomas O Eichmann, Robert Gruber, Franz Pw Radner, Martin Hermann, Barbara Del Frari, Sandrine Dubrac
The skin is in daily contact with environmental pollutants, but the long-term effects of such exposure remain under-investigated. Many of these toxins bind and activate the pregnane x receptor (PXR), a ligand-activated transcription factor that regulates genes central to xenobiotic metabolism. The objective of this work was to investigate the effect of constitutive activation of PXR in the basal layer of the skin to mimic repeated skin exposure to noxious molecules. We designed a transgenic mouse model which overexpresses the human PXR gene linked to the herpes simplex VP16 domain under the control of the keratin 14 promoter...
September 16, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28916285/profiling-of-bisphenol-s-towards-nuclear-receptors-activities-in-human-reporter-cell-lines
#3
Ondrej Zenata, Zdenek Dvorak, Radim Vrzal
Bisphenol S (BPS) is heat-stable structural analog of bisphenol A (BPA), a known endocrine disruptor. Due to the effort to replace BPA with BPS, it is essential to know if BPS is suitable non-toxic replacement without reported deleterious effects of BPA. Since most of the BPA effects are ascribed to its ability to activate nuclear receptors, we screened some prominent members of this family in order to confirm or refute some recent findings. We found that BPS insignificantly activated aryl hydrocarbon receptor (AhR) in reporter gene assay and no induction of AhR target gene CYP1A1 was observed in human hepatocytes (HH)...
September 12, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28911860/glucose-elicits-serine-threonine-kinase-vrk1-to-phosphorylate-nuclear-pregnane-x-receptor-as-a-novel-hepatic-gluconeogenic-signal
#4
Saki Gotoh, Yuu Miyauchi, Rick Moore, Masahiko Negishi
Low glucose stimulated phosphorylation of pregnane X receptor (PXR) at Ser(350) in correlation with an increased gluconeogenesis in human hepatoma-derived HepG2 cells. Only glucose, but neither insulin nor glucagon, stimulated this phosphorylation. Here, serine/threonine kinase, vaccinia related kinase 1 (VRK1)-mediated phosphorylation of PXR is now defined as this glucose-elicited novel signal. In low glucose conditions, VRK1 directly phosphorylates PXR at Ser(350), enabling PO3-PXR to scaffold protein phosphatase PP2Cα...
September 11, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28903501/sex-differential-responses-of-tumor-promotion-associated-genes-and-dysregulation-of-novel-long-noncoding-rnas-in-constitutive-androstane-receptor-activated-mouse-liver
#5
Nicholas J Lodato, Tisha Melia, Andy Rampersaud, David J Waxman
Xenobiotic agonists of constitutive androstane receptor (CAR) induce many hepatic drug metabolizing enzymes, but following prolonged exposure, promote hepatocellular carcinoma, most notably in male mouse liver. Here, we used nuclear RNA-seq to characterize global changes in the mouse liver transcriptome following exposure to the CAR-specific agonist ligand 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), including changes in novel long noncoding RNAs that may contribute to xenobiotic-induced pathophysiology...
September 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28894435/neuroactive-steroids-receptor-interactions-and-responses
#6
REVIEW
Kald Beshir Tuem, Tesfay Mehari Atey
Neuroactive steroids (NASs) are naturally occurring steroids, which are synthesized centrally as de novo from cholesterol and are classified as pregnane, androstane, and sulfated neurosteroids (NSs). NASs modulate many processes via interacting with gamma-aminobutyric acid (GABA), N-methyl-d-aspartate, serotonin, voltage-gated calcium channels, voltage-dependent anion channels, α-adrenoreceptors, X-receptors of the liver, transient receptor potential channels, microtubule-associated protein 2, neurotrophin nerve growth factor, and σ1 receptors...
2017: Frontiers in Neurology
https://www.readbyqxmd.com/read/28890368/cyp17a1-independent-production-of-the-neurosteroid-derived-5%C3%AE-pregnan-3%C3%AE-6%C3%AE-diol-20-one-in-androgen-responsive-prostate-cancer-cell-lines-under-serum-starvation-and-inhibition-by-abiraterone
#7
Antonio G Gomes de Mello Martins, Giuseppe Allegretta, Gerhard Unteregger, Jörg Haupenthal, Jens Eberhard, Michael Hoffmann, Jill A van der Zee, Kerstin Junker, Michael Stöckle, Rolf Müller, Rolf W Hartmann, Carsten-H Ohlmann
CYP17A1-independent intratumoral steroid hormone synthesis is regarded as one possible explanation for resistance to treatment with the CYP17-inhibitor Abiraterone (Abi). The aim of our study was therefore to investigate the steroid metabolism of prostate cancer cells under serum starvation and the effects of Abi treatment. We assessed steroid metabolism in a panel of prostate cancer cells under serum starvation by radioactivity detector-coupled HPLC and HPLC-ESI-ToF-mass spectrometry after treatment with pregnenolone, progesterone and allopregnanolone...
September 7, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28888833/iron-depletion-induces-hepatic-secretion-of-biliary-lipids-and-glutathione-in-rats
#8
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
#9
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/28878092/equine-fetal-adrenal-gonadal-and-placental-steroidogenesis
#10
Erin L Legacki, Barry A Ball, C Jo Corbin, Shavahn C Loux, Kirsten E Scoggin, Scott D Stanley, Alan J Conley
Equine fetuses have substantial circulating pregnenolone concentrations and thus have been postulated to provide significant substrate for placental 5α-reduced pregnane production, but the fetal site of pregnenolone synthesis remains unclear. The current studies investigated steroid concentrations in blood, adrenal glands, gonads and placenta from fetuses (4, 6, 9 and 10 months of gestational age (GA)), as well as tissue steroidogenic enzyme transcript levels. Pregnenolone and dehydroepiandrosterone (DHEA) were the most abundant steroids in fetal blood, pregnenolone was consistently higher but decreased progressively with GA...
October 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/28865089/impact-of-enzalutamide-and-its-main-metabolite-n-desmethyl-enzalutamide-on-pharmacokinetically-important-drug-metabolizing-enzymes-and-drug-transporters
#11
Johanna Weiss, Jutta Kocher, Corina Mueller, Stephanie Rosenzweig, Dirk Theile
Enzalutamide is a new drug against castration-resistant prostate cancer. Recent data indicate profound induction of drug metabolizing enzymes (e.g. cytochrome P450 isoenzyme (CYP) 3A4) but comprehensive in vitro data on other CYP enzymes, drug conjugating enzymes or drug transporters is scarce. Moreover, mechanisms of induction are poorly investigated and the effects of the active metabolite N-desmethyl enzalutamide are unknown. Using LS180 cells as an induction model and quantitative real-time reverse transcription polymerase chain reaction, our study demonstrated a concentration-dependent induction of CYP1A1, CYP1A2, CYP3A5, CYP3A4, UGT1A3, UGT1A9, ABCB1, ABCC2, and ABCG2 mRNA...
September 1, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28833805/carbon-isotope-ratios-of-endogenous-steroids-in-belgian-blue-and-holstein-cattle-method-development-reference-population-studies-and-application-to-steroid-misuse-control
#12
Thomas Piper, Marlen Putz, Phillipe Delahaut, Mario Thevis
RATIONALE: The misuse of growth promoters in livestock and breeding animals is prohibited according to the laws of the European Union. Among these growth promoters, the detection of endogenous steroids like testosterone, estradiol or progesterone remains especially challenging as concentration-based urinary thresholds may not provide conclusive results due to large inter-individual variations. In addition to the detection of intact steroid esters in blood or hair, carbon isotope ratio (CIR) determinations of urinary steroids has commonly been the method of choice...
August 22, 2017: Rapid Communications in Mass Spectrometry: RCM
https://www.readbyqxmd.com/read/28825834/combining-genomics-to-identify-the-pathways-of-post-transcriptional-nongenotoxic-signaling-and-energy-homeostasis-in-livers-of-rats-treated-with-the-pregnane-x-receptor-agonist-pregnenolone-carbonitrile
#13
Hirohisa Nagahori, Kenji Nakamura, Kayo Sumida, Shingo Ito, Sumio Ohtsuki
Transcriptomic, proteomic, phosphoproteomic, and metabolomic analyses were combined to determine the role of pregnane X receptor (PXR) in nongenotoxic signaling and energy homeostasis in liver after rats were repeatedly orally dosed with the PXR agonist pregnenolone carbonitrile (PCN) for 7 days. Analyses of mRNAs and proteins in the supernatant, membrane, and cytosolic fractions of enlarged liver homogenates showed diverse expression profiles. Gene set enrichment analysis showed that the synchronous increase in mRNAs and proteins involved in chemical carcinogenesis and the response to drug was possibly mediated by the PXR pathway and proteasome core complex assembly was possibly mediated by the Nrf2 pathway...
September 6, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28818793/cellular-adaptation-to-xenobiotics-interplay-between-xenosensors-reactive-oxygen-species-and-foxo-transcription-factors
#14
Lars-Oliver Klotz, Holger Steinbrenner
Cells adapt to an exposure to xenobiotics by upregulating the biosynthesis of proteins involved in xenobiotic metabolism. This is achieved largely via activation of cellular xenosensors that modulate gene expression. Biotransformation of xenobiotics frequently comes with the generation of reactive oxygen species (ROS). ROS, in turn, are known modulators of signal transduction processes. FOXO (forkhead box, class O) transcription factors are among the proteins deeply involved in the cellular response to stress, including oxidative stress elicited by the formation of ROS...
August 3, 2017: Redox Biology
https://www.readbyqxmd.com/read/28815300/holaphyllamine-a-steroid-is-able-to-induce-defense-responses-in-arabidopsis-thaliana-and-increases-resistance-against-bacterial-infection
#15
Abderrakib Zahid, Rim Jaber, Ferdousse Laggoun, Arnaud Lehner, Isabelle Remy-Jouet, Olivier Pamlard, Sandra Beaupierre, Jérome Leprince, Marie-Laure Follet-Gueye, Maïté Vicré-Gibouin, Xavier Latour, Vincent Richard, Catherine Guillou, Patrice Lerouge, Azeddine Driouich, Jean-Claude Mollet
A chemical screen of plant-derived compounds identified holaphyllamine, a steroid, able to trigger defense responses in Arabidopsis thaliana and improve resistance against the pathogenic bacterium Pseudomonas syringae pv tomato DC3000. A chemical screen of 1600 plant-derived compounds was conducted and allowed the identification of a steroid able to activate defense responses in A. thaliana at a concentration of 1 µM without altering growth. The identified compound is holaphyllamine (HPA) whose chemical structure is similar to steroid pregnanes of mammals...
August 16, 2017: Planta
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
#16
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/28793934/statin-therapy-causes-gut-dysbiosis-in-mice-through-a-pxr-dependent-mechanism
#17
Jose A Caparrós-Martín, Ricky R Lareu, Joshua P Ramsay, Jörg Peplies, F Jerry Reen, Henrietta A Headlam, Natalie C Ward, Kevin D Croft, Philip Newsholme, Jeffery D Hughes, Fergal O'Gara
BACKGROUND: Statins are a class of therapeutics used to regulate serum cholesterol and reduce the risk of heart disease. Although statins are highly effective in removing cholesterol from the blood, their consumption has been linked to potential adverse effects in some individuals. The most common events associated with statin intolerance are myopathy and increased risk of developing type 2 diabetes mellitus. However, the pathological mechanism through which statins cause these adverse effects is not well understood...
August 9, 2017: Microbiome
https://www.readbyqxmd.com/read/28774496/adrenal-c11-oxy-c21-steroids-contribute-to-the-c11-oxy-c19-steroid-pool-via-the-backdoor-pathway-in-the-biosynthesis-and-metabolism-of-21-deoxycortisol-and-21-deoxycortisone
#18
Lise Barnard, Rachelle Gent, Desmaré van Rooyen, Amanda C Swart
21-Hydroxylase deficiency presents with increased levels of cytochrome P450 21-hydroxylase substrates, progesterone and 17α-hydroxyprogesterone, which have been implicated in the production of androgens via the backdoor pathway. This study shows the biosynthesis of C11-oxy C21 steroids, 21-deoxycortisol and 21-deoxycortisone, and their metabolism by steroidogenic enzymes in the backdoor pathway yielding novel steroid metabolites: 5α-pregnan-11β,17α-diol-3,20-dione; 5α-pregnan-17α-ol-3,11,20-trione; 5α-pregnan-3α,11β,17α-triol-20-one and 5α-pregnan-3α,17α-diol-11,20-dione...
July 31, 2017: Journal of Steroid Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28768576/the-xenobiotic-sensor-pxr-in-a-marine-flatfish-species-solea-senegalensis-gene-expression-patterns-and-its-regulation-under-different-physiological-conditions
#19
Carlos Marques, Vânia P Roberto, Luís Granadeiro, Marlene Trindade, Paulo J Gavaia, Vincent Laizé, M Leonor Cancela, Ignacio Fernández
The pregnane X receptor (PXR) is a nuclear receptor belonging to the NR1I sub-family and a known master regulator of xenobiotic metabolism. New roles have been recently proposed in mammals through its activation by vitamin K (VK) such as regulation of glucose metabolism, bone homeostasis, reproduction, neuronal development and cognitive capacities. In marine fish species little is known about PXR and its potential roles. Here, expression patterns of pxr transcripts and conservation of protein domains were determined in the Senegalese sole (Solea senegalensis), a marine flatfish model species in aquatic ecotoxicology...
July 23, 2017: Marine Environmental Research
https://www.readbyqxmd.com/read/28760623/pregnane-x-receptor-pxr-signaling-in-seabream-primary-hepatocytes-exposed-to-extracts-of-seawater-samples-collected-from-polycyclic-aromatic-hydrocarbons-pahs-contaminated-coastal-areas
#20
Paolo Cocci, Gilberto Mosconi, Francesco Alessandro Palermo
Polycyclic aromatic hydrocarbons (PAHs) are persistent organic pollutants damaging to the marine environment and the wildlife. Herein, we investigated the effects of extracts from coastal seawaters (central Adriatic sea, Italy), showing high concentrations of PAHs, on pregnane X receptor (PXR)-transcriptional regulation of the cytochrome P450 3A (CYP3A) gene using seabream primary hepatocytes. The results show that concentrated extracts of seawater with original ΣPAH concentrations above the putative threshold of 30 ng L(-1) increased expression of PXR and its main target gene, CYP3A...
July 19, 2017: Marine Environmental Research
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