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https://www.readbyqxmd.com/read/28818793/cellular-adaptation-to-xenobiotics-interplay-between-xenosensors-reactive-oxygen-species-and-foxo-transcription-factors
#1
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/28812950/expression-of-cytochrome-p450-regulators-in-cynomolgus-macaque
#2
Yasuhiro Uno, Hiroshi Yamazaki
1. Cytochrome P450 (P450) regulators including nuclear receptors and transcription factors have not been fully investigated in cynomolgus macaques, an important species used in drug metabolism studies. In this study, we analyzed seventeen P450 regulators by sequence and phylogenetic analysis, and tissue expression. 2. Gene and genome structures of seventeen P450 regulators were similar to the human orthologs, and the deduced amino acid sequences showed high sequence identities (92-95%) and more closely clustered, with the human orthologs...
August 16, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28804711/annotation-of-the-nuclear-receptors-in-an-estuarine-fish-species-fundulus-heteroclitus
#3
William S Baldwin, W Tyler Boswell, Gautam Ginjupalli, Elizabeth J Litoff
The nuclear receptors (NRs) are ligand-dependent transcription factors that respond to various internal as well as external cues such as nutrients, pheromones, and steroid hormones that play crucial roles in regulation and maintenance of homeostasis and orchestrating the physiological and stress responses of an organism. We annotated the Fundulus heteroclitus (mummichog; Atlantic killifish) nuclear receptors. Mummichog are a non-migratory, estuarine fish with a limited home range often used in environmental research as a field model for studying ecological and evolutionary responses to variable environmental conditions such as salinity, oxygen, temperature, pH, and toxic compounds because of their hardiness...
2017: Nuclear Receptor Research
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
#4
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
#5
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/28790348/use-antibiotics-in-cell-culture-with-caution-genome-wide-identification-of-antibiotic-induced-changes-in-gene-expression-and-regulation
#6
Ann H Ryu, Walter L Eckalbar, Anat Kreimer, Nir Yosef, Nadav Ahituv
Standard cell culture guidelines often use media supplemented with antibiotics to prevent cell contamination. However, relatively little is known about the effect of antibiotic use in cell culture on gene expression and the extent to which this treatment could confound results. To comprehensively characterize the effect of antibiotic treatment on gene expression, we performed RNA-seq and ChIP-seq for H3K27ac on HepG2 cells, a human liver cell line commonly used for pharmacokinetic, metabolism and genomic studies, cultured in media supplemented with penicillin-streptomycin (PenStrep) or vehicle control...
August 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28772355/environmentally-relevant-levels-of-%C3%AE-cyhalothrin-fenvalerate-and-permethrin-cause-developmental-toxicity-and-disrupt-endocrine-system-in-zebrafish-danio-rerio-embryo
#7
Quan Zhang, Yi Zhang, Jie Du, Meirong Zhao
Synthetic pyrethroids (SPs) are one of the most widely used pesticides and frequently detected in the aquatic environment. Previous studies have shown that SPs posed high aquatic toxicity, but information on the developmental toxicity and endocrine disruption on zebrafish (Danio rerio) at environmentally relevant concentrations is limited. In this study, zebrafish embryos were employed to examine the adverse effects of λ-cyhalothrin (LCT), fenvalerate (FEN), and permethrin (PM) at 2.5, 10, 25, 125, 500 nM for 96 h...
October 2017: Chemosphere
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
#8
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
#9
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
https://www.readbyqxmd.com/read/28756207/pregnane-x-receptor-pxr-deficiency-improves-high-fat-diet-induced-obesity-via-induction-of-fibroblast-growth-factor-15-fgf15-expression
#10
Li-Yang Zhao, Jia-Yi Xu, Zhe Shi, Neal A Englert, Shu-Yun Zhang
Obesity has become a significant global health problem, and is a high risk factor for a variety of metabolic diseases. Fibroblast growth factor (FGF) 15 plays an important role in the regulation of metabolism. Xenobiotic-sensing nuclear receptors pregnane X receptor (PXR/NR1I2) and constitutive androstane receptor (CAR/NR1I3) play important roles in xenobiotic detoxification and metabolism, and also are involved in the regulation of energy metabolism. However, the effects that PXR and CAR have on the regulation of FGF15 are unknown...
July 26, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28743453/pregnane-x-receptor-deletion-modifies-recognition-memory-and-electroencephalographic-activity
#11
Badreddine Boussadia, Laila Lakhal, Laurence Payrastre, Chaitali Ghosh, Jean-Marc Pascussi, Giuseppe Gangarossa, Nicola Marchi
Nuclear receptors (NR) are emerging as key players in the central nervous system (CNS) with reported implications in physiological and pathophysiological conditions. While a number of NR has been studied, it is unknown whether invalidation of the pregnane xenobiotic receptor (PXR, NR1I2) corresponds to neurological modifications in the adult brain. PXR(-/-) C57BL/6J and wild-type mice were used to investigate: (i) recognition memory, motor coordination, and anxiety-like behaviors; (ii) longitudinal video-electroencephalographic (EEG) recordings and frequency wave analysis; (iii) neurovascular structures by histological evaluation and expression of the cerebrovascular tight junctions ZO1 and CLDN5...
July 23, 2017: Neuroscience
https://www.readbyqxmd.com/read/28742404/pregnane-x-receptor-polymorphisms-and-risk-of-inflammatory-bowel-disease-a-meta-analysis
#12
Xiaolan Guo, Ming Yan
BACKGROUND: Pregnane X receptor (PXR) gene polymorphisms have been widely studied in terms of the association with inflammatory bowel disease (IBD), with inconsistent results. OBJECTIVE: The present meta-analysis was performed to assess the association between PXR gene polymorphisms and the susceptibility of IBD, Crohn's disease (CD), and ulcerative colitis (UC). METHODS: PubMed, Wanfang, and CNKI databases were searched for eligible studies before November 1, 2016...
August 2017: Immunological Investigations
https://www.readbyqxmd.com/read/28716828/creation-and-preliminary-characterization-of-pregnane-x-receptor-and-constitutive-androstane-receptor-knockout-rats
#13
Kevin P Forbes, Evguenia Kouranova, Daniel Tinker, Karen Janowski, Doug Cortner, Aaron McCoy, Xiaoxia Cui
The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are closely related transcription factors that regulate the expression of Phase I (Cytochrome P450s), Phase II metabolizing enzymes and transporter genes in response to stimulation from xenobiotics, including prescription drugs. PXR and CAR are also involved in other endogenous processes, such as in inflammation, glucose homeostasis and lipid metabolism, and are thus potential drug targets themselves. PXR and CAR knockout and humanized mouse models have proven useful...
July 17, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28699014/predictive-models-for-identifying-the-binding-activity-of-structurally-diverse-chemicals-to-human-pregnane-x-receptor
#14
Cen Yin, Xianhai Yang, Mengbi Wei, Huihui Liu
Toxic chemicals entered into human body would undergo a series of metabolism, transport and excretion, and the key roles played in there processes were metabolizing enzymes, which was regulated by the pregnane X receptor (PXR). However, some chemicals in environment could activate or antagonize human pregnane X receptor, thereby leading to a disturbance of normal physiological systems. In this study, based on a larger number of 2724 structurally diverse chemicals, we developed qualitative classification models by the k-nearest neighbor method...
July 12, 2017: Environmental Science and Pollution Research International
https://www.readbyqxmd.com/read/28698304/prediction-of-clinically-relevant-herb-drug-clearance-interactions-using-a-whole-cell-approach-schisandra-sphenanthera-case-study
#15
Jonathan P Jackson, Kimberly M Freeman, Weslyn W Friley, Ashley G Herman, Christopher B Black, Kenneth R Brouwer, Amy L Roe
The Schisandraceae family is reported to have a range of pharmacological activities, including anti-inflammatory effects. As with all herbal preparations, extracts of Schisandra species are mixtures composed of >50 lignans including schizandrins and deoxyschizandrins. In China, Schisandra sphenanthera extract (SSE) is often co-administered with immunosuppressant treatment of transplant recipients. In cases of co-administration, the potential for herb-drug interactions (HDI) increases. Clinical studies have been employed to assess HDI of extracts including SSE...
July 11, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28685622/induction-of-human-cytochrome-p450-3a4-by-the-irreversible-myeloperoxidase-inactivator-pf-06282999-is-mediated-by-the-pregnane-x-receptor
#16
Jamie E Moscovitz, Zhiwu Lin, Nathaniel Johnson, Meihua Tu, Theunis Goosen, Yan Weng, Amit S Kalgutkar
1. 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamide (PF-06282999) is a member of the thiouracil class of irreversible inactivators of human myeloperoxidase enzyme and a candidate for the treatment of cardiovascular disease. PF-06282999 is an inducer of CYP3A4 mRNA and midazolam-1'-hydroxylase activity in human hepatocytes, which is consistent with PF-06282999-dose dependent decreases in mean maximal plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) of midazolam in humans following 14-day treatment with PF-06282999...
July 7, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28682217/simvastatin-modulates-gene-expression-of-key-receptors-in-zebrafish-embryos
#17
V Cunha, M M Santos, P Moradas-Ferreira, L F C Castro, M Ferreira
Nuclear receptors (NR) are involved in the regulation of several metabolic processes and it is well known that these constituents may be modulated by different chemicals classes, including pharmaceuticals that may activate or antagonize NR. In mammals, some pharmaceuticals modulate the transcription of pregnane X receptor, Pxr, peroxisome proliferator activated receptor, Ppars, and aryl hydrocarbon receptor, Ahr, affecting mRNA expression of genes belonging to various regulatory pathways, including lipid metabolism and detoxification mechanisms...
July 6, 2017: Journal of Toxicology and Environmental Health. Part A
https://www.readbyqxmd.com/read/28678150/metabolism-of-the-marine-phycotoxin-ptx-2-and-its-effects-on-hepatic-xenobiotic-metabolism-activation-of-nuclear-receptors-and-modulation-of-the-phase-i-cytochrome-p450
#18
Jimmy Alarcan, Estelle Dubreil, Antoine Huguet, Dominique Hurtaud-Pessel, Stefanie Hessel-Pras, Alfonso Lampen, Valérie Fessard, Ludovic Le Hegarat
PTX-2 is a marine biotoxin frequently found in shellfish that can lead to food intoxication in humans. Information regarding PTX-2 metabolism is scarce, and little is known of its effect on xenobiotic-metabolizing enzymes (XME) or its molecular pathways. The aim of this study was consequently to examine PTX-2 Phase I metabolism using rat and human liver S9 fractions, and also to assess the capability of PTX-2: (i) to modulate the gene expression of a panel of Phase I (CYP450) and II (UGT, SULT, NAT, and GST) enzymes, as well as the Phase III or 0 (ABC and SLCO) transporters in the human hepatic HepaRG cell line using qPCR; (ii) to induce specific CYP450 in HepaRG cells measured by immunolabeling detection and the measurement of the cells' activities; and (iii) to activate nuclear receptors and induce CYP promoter activities in HEK-T and HepG2 transfected cell lines using transactivation and reporter gene assay, respectively...
July 5, 2017: Toxins
https://www.readbyqxmd.com/read/28676933/association-of-nr1i2-cyp3a5-and-abcb1-genetic-polymorphisms-with-variability-of-temsirolimus-pharmacokinetics-and-toxicity-in-patients-with-metastatic-bladder-cancer
#19
Litaty C Mbatchi, Matthieu Gassiot, Philippe Pourquier, Alejando Goberna, Hakim Mahammedi, Loic Mourey, Florence Joly, Serge Lumbroso, Alexandre Evrard, Nadine Houede
PURPOSE: Temsirolimus is a mammalian target of rapamycin (mTOR) inhibitor that exhibits antitumor activity in renal cell carcinoma and mantle cell lymphoma. The metabolism of temsirolimus and its active metabolite sirolimus mainly depends on cytochrome P450 3A4/5 (CYP3A4/A5) and the ABCB1 transporter. Differently from sirolimus, no pharmacogenetic study on temsirolimus has been conducted. Therefore, the aim of this pilot study was to identify genetic determinants of the inter-individual variability in temsirolimus pharmacokinetics and toxicity...
July 4, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28674261/preliminary-evaluation-of-three-dimensional-primary-human-hepatocyte-culture-system-for-assay-of-drug-metabolizing-enzyme-inducing-potential
#20
Hiroshi Arakawa, Hiroki Kamioka, Tomoko Jomura, Satoshi Koyama, Yoko Idota, Kentaro Yano, Hajime Kojima, Takuo Ogihara
Drug-induced liver injury (DILI) is a common reason for withdrawal of candidate drugs from clinical trials, or of approved drugs from the market. DILI may be induced not only by intact parental drugs, but also by metabolites or intermediates, and therefore should be evaluated in the enzyme-induced state. Here, we present a protocol for assay of drug-metabolizing enzyme-inducing potential using three-dimensional (3D) primary cultures of human hepatocytes (hepatocyte spheroids). Hepatocyte spheroids could be used up to 21 d after seeding (pre-culture for 7 d and exposure to inducer for up to 14 d), based on preliminary evaluation of basal activities of CYP subtypes and mRNA expression of the corresponding transcription factor and xenobiotic receptors (aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) and pregnane X receptor (PXR))...
2017: Biological & Pharmaceutical Bulletin
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