- MeSH
- antioxidancia * izolace a purifikace metabolismus normy MeSH
- bilirubin * izolace a purifikace krev metabolismus MeSH
- cholestáza * etiologie klasifikace metabolismus MeSH
- komorbidita MeSH
- kyselina cholová chemie metabolismus MeSH
- lidé MeSH
- metaanalýza jako téma MeSH
- receptory cytoplazmatické a nukleární metabolismus MeSH
- statistika jako téma MeSH
- žluč metabolismus MeSH
- žlučové kyseliny a soli chemie metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
The Pregnane X (PXR), Vitamin D (VDR) and Farnesoid X (FXR) nuclear receptors have been shown to be receptors of bile acids controlling their detoxification or synthesis. Chenodeoxycholic (CDCA) and lithocholic (LCA) acids are ligands of FXR and VDR, respectively, whereas 3-keto and acetylated derivates of LCA have been described as ligands for all three receptors. In this study, we hypothesized that oxidation or acetylation at position 3, 7 and 12 of bile acids DCA (deoxycholic acid), LCA, CA (cholic acid), and CDCA by detoxification enzymes or microbiome may have an effect on the interactions with bile acid nuclear receptors. We employed reporter gene assays in HepG2 cells, the TR-FRET assay with recombinant PXR and RT-PCR to study the effects of acetylated and keto bile acids on the nuclear receptors activation and their target gene expression in differentiated hepatic HepaRG cells. We demonstrate that the DCA 3,12-diacetate and CA 3,7,12-triacetate derivatives are ligands of PXR and DCA 3,12-diacetate induces PXR target genes such as CYP3A4, CYP2B6 and ABCB1/MDR1. In conclusion, we found that acetylated DCA and CA are potent ligands of PXR. Whether the acetylated bile acid derivatives are novel endogenous ligands of PXR with detoxification or physiological functions should be further studied in ongoing experiments.
- MeSH
- acetylace MeSH
- buněčné kultury MeSH
- buňky Hep G2 MeSH
- cytochrom P-450 CYP3A genetika MeSH
- cytochrom P450 CYP2B6 genetika MeSH
- hepatocyty účinky léků enzymologie metabolismus MeSH
- kyselina cholová chemie metabolismus farmakologie MeSH
- kyselina deoxycholová chemie metabolismus farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- myši MeSH
- oxidace-redukce MeSH
- P-glykoprotein genetika MeSH
- plazmidy MeSH
- receptory cytoplazmatické a nukleární chemie genetika metabolismus MeSH
- receptory kalcitriolu chemie genetika metabolismus MeSH
- reportérové geny MeSH
- simulace molekulového dockingu MeSH
- steroidní receptory chemie genetika metabolismus MeSH
- techniky dvojhybridového systému MeSH
- transfekce MeSH
- vazba proteinů MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Structure validation has become a major issue in the structural biology community, and an essential step is checking the ligand structure. This paper introduces MotiveValidator, a web-based application for the validation of ligands and residues in PDB or PDBx/mmCIF format files provided by the user. Specifically, MotiveValidator is able to evaluate in a straightforward manner whether the ligand or residue being studied has a correct annotation (3-letter code), i.e. if it has the same topology and stereochemistry as the model ligand or residue with this annotation. If not, MotiveValidator explicitly describes the differences. MotiveValidator offers a user-friendly, interactive and platform-independent environment for validating structures obtained by any type of experiment. The results of the validation are presented in both tabular and graphical form, facilitating their interpretation. MotiveValidator can process thousands of ligands or residues in a single validation run that takes no more than a few minutes. MotiveValidator can be used for testing single structures, or the analysis of large sets of ligands or fragments prepared for binding site analysis, docking or virtual screening. MotiveValidator is freely available via the Internet at http://ncbr.muni.cz/MotiveValidator.
There were synthesized new types of ribbon type steroidal dimers derived from three types of steroidal skeletons (cholic acid, etienic acid, estrone) using Cu(I) catalyzed 1, 3-dipolar cycloaddition reaction. Steroid parts of the molecular "ribbons" are linked by heterocyclic moiety, namely by 2,6-bis((1H-1,2,3-triazol-1-yl)-methyl)pyridine. Compounds synthesized possess different cytotoxic and hormone receptor modulating activities.
- MeSH
- androsteny chemie MeSH
- antagonisté hormonů chemická syntéza farmakologie MeSH
- cytotoxiny chemická syntéza farmakologie MeSH
- estron chemie MeSH
- katalýza MeSH
- kyselina cholová chemie MeSH
- lidé MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- pyridiny chemie MeSH
- steroidní receptory antagonisté a inhibitory metabolismus MeSH
- steroidy chemická syntéza farmakologie MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
New cholic acid based calix[4]pyrroles and porphyrins were prepared and their properties were studied. It was confirmed by spectral measurements that the superassembly of 5,15-bis(3α,7α,12α-trihydroxy-5β-cholan-24-yl)-10,20-diphenylporphyrin, the best candidate for this study from the conjugates prepared, may be influenced not only by the solvent mixture composition (polar/non-polar component ratio) but by time as well.
Skin penetration enhancers are used in the formulation of transdermal delivery systems for drugs that are otherwise not sufficiently skin-permeable. Intestinal absorption promoters/enhancers are used as excipients in oral formulations of poorly oral-bioavailable drugs. Series of fourteen acyloxy derivatives of 5β-cholic acid as potential drug absorption modifiers was generated by multistep synthesis. The synthesis of all newly prepared compounds is presented here. Structure confirmation of all generated compounds was accomplished by (1)H NMR, (13)C NMR, IR and MS spectroscopy methods. All the prepared compounds were analyzed using RP-TLC, and their lipophilicity (R(M)) was determined. The hydrophobicity (logP) and solubility (logS) of the studied compounds were also calculated using two commercially available programs. All the target compounds were tested for their in vitro transdermal penetration activity and as potential intestinal absorption enhancers. The anti-proliferative activity of all the final compounds was also assessed against the human cancer cell lines: T-lymphoblastic leukemia cell line and the breast adenocarcinoma cell line. Their cytotoxicity was also evaluated against the normal human skin fibroblast cells. Two compounds showed anti-proliferative effect on cancer cells without affecting the growth of normal cells, which should be promising in potential development of new drugs. Most of the target compounds showed minimal anti-proliferative activity (IC(50)>37 μM), indicating they would have low cytotoxicity when administered as chemical absorption modifiers. The relationships between the lipophilicity and the chemical structure of the studied compounds as well as the relationships between their chemical structure and enhancement effects are discussed in this article.
- MeSH
- buněčné linie MeSH
- estery škodlivé účinky chemie MeSH
- hydrofobní a hydrofilní interakce MeSH
- kožní absorpce účinky léků MeSH
- kůže účinky léků metabolismus MeSH
- kyselina cholová škodlivé účinky chemie MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- nádorové buněčné linie MeSH
- pomocné látky škodlivé účinky chemie MeSH
- prasata MeSH
- theofylin chemie farmakokinetika MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
