Teriflunomide Is an Indirect Human Constitutive Androstane Receptor (CAR) Activator Interacting With Epidermal Growth Factor (EGF) Signaling

The constitutive androstane receptor (CAR) is a nuclear receptor involved mainly in xenobiotic and endobiotic metabolism regulation. CAR is activated directly by its ligands via the ligand binding domain (LBD) or indirectly by inhibition of the epidermal growth factor (EGF) signaling. We found that leflunomide (LEF) and its main metabolite teriflunomide (TER), both used for autoimmune diseases treatment, induce the prototype CAR target gene CYP2B6 in primary human hepatocytes. As TER was discovered to be an EGF receptor antagonist, we sought to determine if TER is an indirect activator of CAR. In primary human hepatocytes and in differentiated HepaRG cells, we found that LEF and TER up-regulate CAR target genes CYP2B6 and CYP3A4 mRNAs and enzymatic activities. TER stimulated CAR+A mutant translocation into the nucleus but neither LEF nor TER activated the CAR LBD, CAR3 variant or pregnane X receptor (PXR) in gene reporter assays. Interestingly, TER significantly up-regulated CAR mRNA expression, a result which could be a consequence of both EGF receptor and ELK-1 transcription factor inhibition by TER or by TER-mediated activation of glucocorticoid receptor (GR), an upstream hormonal regulator of CAR. We can conclude that TER is a novel indirect CAR activator which through EGF inhibition and GR activation controls both detoxification and some intermediary metabolism genes

The mechanisms of pharmacokinetic food-drug interactions: A perspective from the UNGAP group

The simultaneous intake of food and drugs can have a strong impact on drug release, absorption, distribution, metabolism and/or elimination and consequently, on the efficacy and safety of pharmacotherapy. As such, food-drug interactions are one of the main challenges in oral drug administration. Whereas pharmacokinetic (PK) food-drug interactions can have a variety of causes, pharmacodynamic (PD) food-drug interactions occur due to specific pharmacological interactions between a drug and particular drinks or food. In recent years, extensive efforts were made to elucidate the mechanisms that drive pharmacokinetic food-drug interactions. Their occurrence depends mainly on the properties of the drug substance, the formulation and a multitude of physiological factors. Every intake of food or drink changes the physiological conditions in the human gastrointestinal tract. Therefore, a precise understanding of how different foods and drinks affect the processes of drug absorption, distribution, metabolism and/or elimination as well as formulation performance is important in order to be able to predict and avoid such interactions. Furthermore, it must be considered that beverages such as milk, grapefruit juice and alcohol can also lead to specific food-drug interactions. In this regard, the growing use of food supplements and functional food requires urgent attention in oral pharmacotherapy. Recently, a new consortium in Understanding Gastrointestinal Absorption-related Processes (UNGAP) was established through COST, a funding organisation of the European Union supporting translational research across Europe. In this review of the UNGAP Working group "Food-Drug Interface", the different mechanisms that can lead to pharmacokinetic food-drug interactions are discussed and summarised from different expert perspective

Analysis of the technical security physical protection of the school building in the village Písařov

Import 05/08/2014Bakalářská práce se zabývá zvýšením míry zabezpečení školního typu objektu, ve kterém se nachází základní a mateřská škola v obci Písařov. V první části jsou uvedeny právní předpisy a technické normy. Dále se práce zaměřuje na teorii fyzické ochrany, na popis objektu a dosavadní zabezpečení. Následuje vytipování slabých článků systému, návrh nového zabezpečení a jeho technickou realizaci a ekonomickou náročnost.The bachelor thesis deals with increasing of the security of school type object, in which is situated primary and nursery school in the village Písařov. The first section describes the regulations and technical standards. The thesis also focuses on the theory of physical protection, the description of the object and the existing security. Followed by the identification of weak links in the system, the design of the new security and its technical realization and economic cost.Prezenční060 - Katedra bezpečnostních služebvelmi dobř

Physical protection of the municipal office in Písařov

PÁVEK, Petr. Systémy fyzické ochrany objektu Obecního úřadu v Písařově. Diplomová práce. Ostrava, 2017. 57 s. VŠB – Technická univerzita Ostrava, Fakulta bezpečnostního inženýrství. Vedoucí diplomové práce doc. RNDr. Karla Barčová, Ph.D. Předmětem této diplomové práce jsou systémy fyzické ochrany objektu Obecního úřadu v Písařově. Cílem práce je zjistit a popsat za využití vybraných analytických metod a hodnocení bezpečnostních rizik aktuální rizika spojená s fyzickou ochranou objektu Obecního úřadu v obci Písařov. Na základě teoretických znalostí a praktických poznatků budou navržena inovativní řešení ochrany tohoto objektu se zaměřením na investiční náklady, kvalitu zabezpečení a estetické nároky. Navržená opatření budou vyhotovena ve třech variantách a varianty mezi sebou porovnány. Následně bude vyhodnocena výsledná varianta inovativního zabezpečení.PÁVEK, Petr. Physical protection of the municipal office in Písařov. Diploma thesis. Ostrava, 2017. 57 s. VSB – Technical University of Ostrava, Faculty of Safety Engineering. Thesis supervisor doc. RNDr. Karla Barčová, Ph.D. The subject of this thesis are systems of physical protection of the building of the Municipal Office in Písařov. The aim is to identify and describe using the selected analytical methods and safety risk assessment of the current risks associated with the physical protection of the Municipal Office Building in the village Písařov. On the basis of theoretical knowledge and practical knowledge will be proposed innovative solutions to protect this object, focusing on investment cost, quality, security and aesthetic demands. The proposed measures will be made in three variants and variants compared with each other. Subsequently, the resulting variant will be evaluated innovative security.060 - Katedra bezpečnostních služebdobř

Influence of parents on their children's sports activities

Ústav profesního rozvoje pracovníků ve školstvíFaculty of EducationPedagogická fakult

Finanční analýza Českého Telecomu, a.s.

Práce se snaží zanalyzovat finanční situaci společnosti Český Telecom a na jejím základě navrhnout vhodná opatření, která by zásadním způsobem zlepšila finanční zdraví podniku, zejména v kontextu prohlubujícího se konkurenčního prostředí, které lze sledovat v posledních letech v České Republice

The Use of the LanthaScreen TR-FRET CAR Coactivator Assay in the Characterization of Constitutive Androstane Receptor (CAR) Inverse Agonists

The constitutive androstane receptor (CAR) is a critical nuclear receptor in the gene regulation of xenobiotic and endobiotic metabolism. The LanthaScreenTM TR-FRET CAR coactivator assay provides a simple and reliable method to analyze the affinity of a ligand to the human CAR ligand-binding domain (LBD) with no need to use cellular models. This in silico assay thus enables the study of direct CAR ligands and the ability to distinguish them from the indirect CAR activators that affect the receptor via the cell signaling-dependent phosphorylation of CAR in cells. For the current paper we characterized the pharmacodynamic interactions of three known CAR inverse agonists/antagonists—PK11195, clotrimazole and androstenol—with the prototype agonist CITCO (6-(4-chlorophenyl)imidazo[2,1-b][1,3] thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime) using the TR-FRET LanthaScreenTM assay. We have confirmed that all three compounds are inverse agonists of human CAR, with IC50 0.51, 0.005, and 0.35 μM, respectively. All the compounds also antagonize the CITCO-mediated activation of CAR, but only clotrimazole was capable to completely reverse the effect of CITCO in the tested concentrations. Thus this method allows identifying not only agonists, but also antagonists and inverse agonists for human CAR as well as to investigate the nature of the pharmacodynamic interactions of CAR ligands