Latest Publications

@article{sladekova_switching_2023,

title = {Switching on/off aryl hydrocarbon receptor and pregnane X receptor activities by chemically modified tryptamines.},

author = {Lucia Sládeková and Eliška Zgarbová and Radim Vrzal and David Vanda and Miroslav Soural and Klára Jakubcová and Gerardo Vázquez-Gómez and Jan Vondráček and Zdeněk Dvořák},

doi = {10.1016/j.toxlet.2023.09.012},

issn = {1879-3169 0378-4274},

year  = {2023},

date = {2023-09-01},

journal = {Toxicology letters},

volume = {387},

pages = {63–75},

abstract = {Microbial indoles have been demonstrated as selective or dual agonists and ligands of the pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR). However, structural determinants of microbial indoles selectivity towards both receptors remain elusive. Here, we studied the effects of existing and newly synthesized derivatives of indole microbial metabolite tryptamine on the activity of AhR and PXR receptors. We show that the elongation of indolyl-3-alkaneamine chain, indole N-methylation and conversion of indolyl-3-alkaneamines to oleamides resulted in a major increase of PXR activity and in parallel loss of AhR activity. Using reporter gene assays, RT-PCR and TR-FRET techniques, we have characterized in detail the activation of PXR by novel indolyl-3-alkanyl-oleamides, 1-methyltryptamine and 1-methyltryptamine-acetamide. As a proof of concept, we demonstrated anti-inflammatory and epithelial barrier-protective activity of lead derivatives in intestinal Caco-2 cells, employing the measurement of expression of pro-inflammatory chemokines, tight junction genes, trans-epithelial electric resistance TEER, and dextran-FITC permeability assay. In conclusion, we show that a subtle chemical modifications of simple microbial indole metabolite tryptamine, leads to substantial changes in AhR and PXR agonist activities.},

note = {Place: Netherlands},

keywords = {*Receptors, Aryl hydrocarbon receptor, Aryl Hydrocarbon/metabolism, Caco-2 Cells, Humans, Indoles/pharmacology, Microbial indoles, Pregnane X receptor, Pregnane X Receptor/genetics, Steroid/metabolism, Tryptamine, Tryptamines/pharmacology},

pubstate = {published},

tppubtype = {article}

}

@article{andrysik_aryl_2013,

title = {Aryl hydrocarbon receptor-mediated disruption of contact inhibition is associated with connexin43 downregulation and inhibition of gap junctional intercellular communication.},

author = {Zdeněk Andrysík and Jiřina Procházková and Markéta Kabátková and Lenka Umannová and Pavlína Simečková and Jiří Kohoutek and Alois Kozubík and Miroslav Machala and Jan Vondráček},

doi = {10.1007/s00204-012-0963-7},

issn = {1432-0738 0340-5761},

year  = {2013},

date = {2013-03-01},

journal = {Archives of toxicology},

volume = {87},

number = {3},

pages = {491–503},

abstract = {The aryl hydrocarbon receptor (AhR) contributes to the control of cell-to-cell communication, cell adhesion, migration or proliferation. In the present study, we investigated the regulation of connexin43 (Cx43) and Cx43-mediated gap junctional intercellular communication (GJIC) during the AhR-dependent disruption of contact inhibition in non-tumorigenic liver epithelial cells. The contact inhibition of cell proliferation is a process restricting the cell division of confluent non-transformed cells, which is frequently abolished in cancer cells; however, the mechanisms contributing to its disruption are still only partially understood. Disruption of contact inhibition, which was induced by toxic AhR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or polycyclic aromatic hydrocarbons in epithelial WB-F344 cells, reduced Cx43 protein levels, possibly via enhanced proteasomal degradation, significantly decreased the amount of gap junction plaques and downregulated GJIC, in an AhR-dependent manner. Although both intracellular and membrane Cx43 pools were markedly reduced in cells released from contact inhibition by TCDD, siRNA-mediated Cx43 knock-down was not sufficient to stimulate proliferation in contact-inhibited cells. Our data suggest that downregulation of Cx43/GJIC in non-transformed epithelial cells is an inherent part of disruption of contact inhibition, which occurs at the post-transcriptional level. This process runs in parallel with alterations of other forms of cell-to-cell communication, thus suggesting that toxic AhR agonists may simultaneously abrogate contact inhibition and reduce GJIC, two essential mechanisms linked to deregulation of cell-to-cell communication during tumor promotion and progression.},

note = {Place: Germany},

keywords = {Animals, Aryl Hydrocarbon/*agonists/genetics/metabolism, Benz(a)Anthracenes/toxicity, Carcinogens/*toxicity, Cell Communication/*drug effects, Cell Line, Cell Proliferation, Cell Transformation, Connexin 43/genetics/*metabolism, Contact Inhibition/*drug effects, Dose-Response Relationship, Down-Regulation, Drug, Epithelial Cells/*drug effects/metabolism/pathology, Fluorenes/toxicity, Gap Junctions/*drug effects/metabolism/pathology, Gene Knockdown Techniques, Indoles/pharmacology, Ligands, Liver Neoplasms/chemically induced/metabolism/pathology, Liver/*drug effects/metabolism/pathology, Neoplastic/chemically induced/metabolism/pathology, Phloroglucinol/analogs & derivatives/pharmacology, Phosphorylation, Polychlorinated Dibenzodioxins/toxicity, Proteasome Endopeptidase Complex/metabolism, Rats, Receptors, RNA Interference, Signal Transduction/*drug effects, Time Factors, Transfection},

pubstate = {published},

tppubtype = {article}

}

@article{stixova_5-lipoxygenase_2009,

title = {5-Lipoxygenase inhibitors potentiate 1alpha,25-dihydroxyvitamin D3-induced monocytic differentiation by activating p38 MAPK pathway.},

author = {Lenka Stixová and Jirina Procházková and Karel Soucek and Jirina Hofmanová and Alois Kozubík},

doi = {10.1007/s11010-009-0138-x},

issn = {1573-4919 0300-8177},

year  = {2009},

date = {2009-10-01},

journal = {Molecular and cellular biochemistry},

volume = {330},

number = {1-2},

pages = {229–238},

abstract = {The treatment of human promyelocytic leukemia cell lines HL-60, and to some extent NB-4, with 1alpha,25-dihydroxyvitamin D(3) (VD3) induces differentiation toward the monocytic/macrophage lineage, demonstrated by the increased expression of CD11b and CD14, and the production of opsonized zymosan particles (OZP)-stimulated reactive oxygen species (ROS). Moreover, in more sensitive HL-60 cells, increased expression of 5-lipoxygenase (5-LPO), Mcl-1, IkappaB, and c-Jun, accompanied by the activation of p38 MAPK, was detected. These VD3 effects on HL-60 cell differentiation were significantly potentiated by 5-LPO inhibitors MK-886 and AA-861 and were inverted by SB202190 (SB), a p38 MAPK inhibitor. The inhibition of differentiation by SB was demonstrated by a reduction of CD14 expression and by a decrease in OZP-activated ROS production. These results indicated that p38 MAPK pathway is involved in 5-LPO inhibitors-dependent potentiation of VD3-induced monocytic differentiation.},

note = {Place: Netherlands},

keywords = {Arachidonate 5-Lipoxygenase/*genetics, Benzoquinones/pharmacology, Cell Differentiation/*drug effects, HL-60 Cells, Humans, Indoles/pharmacology, Lipoxygenase Inhibitors/*pharmacology, Monocytes/*cytology, p38 Mitogen-Activated Protein Kinases/*metabolism, Vitamin D/*analogs & derivatives/pharmacology},

pubstate = {published},

tppubtype = {article}

}

@article{pachernik_multiple_2002,

title = {Multiple biological effects of inhibitors of arachidonic acid metabolism on human keratinocytes.},

author = {Jirí Pacherník and Ales Hampl and Karel Soucek and Martina Kovaríková and Zdenek Andrysík and Jirina Hofmanová and Alois Kozubík},

doi = {10.1007/s00403-001-0288-5},

issn = {0340-3696},

year  = {2002},

date = {2002-02-01},

journal = {Archives of dermatological research},

volume = {293},

number = {12},

pages = {626–633},

abstract = {BACKGROUND: Various compounds that inhibit processing of arachidonic acid (AA) are being intensively tested for their antitumour activity. However, the mechanisms responsible for such activity remain rather elusive. To approach this issue, we examined the effects of several structurally different inhibitors of AA metabolism in the human keratinocyte HaCaT cell line. METHODS: Several parameters were determined in HaCaT cells exposed to increasing concentrations of the inhibitors for 24 and/or 48 h. These included (1) oxidoreductase activity, total protein mass and cell cycle distribution to assess cell proliferation, (2) degradation of PARP protein to assess apoptosis, and (3) cell morphology, distribution of F-actin and expression of cytokeratins and E-cadherin to evaluate changes in differentiation status. RESULTS: While eicosatetraynoic acid (ETYA), nordihydroguaiaretic acid (NDGA), esculetin and MK-886 reduced proliferation of HaCaT cells, the cyclooxygenase inhibitors indomethacin and piroxicam had no such effects. Esculetin and NDGA arrested cells in S phase, and ETYA and MK-886 delayed cell progression through G(1) phase. Higher concentrations of NDGA, MK886 and/or ETYA caused cleavage of PARP. No changes in the expression of cytokeratins and E-cadherin were observed upon treatment with any of the inhibitors. However, esculetin induced redistribution of F-actin accompanied by increased cell adhesion and size. CONCLUSION: Our findings indicate that, in addition to their ability to inhibit cell proliferation and to induce apoptosis, lipoxygenase inhibitors and/or ETYA may also elicit other important physiological responses in HaCaT keratinocytes.},

note = {Place: Germany},

keywords = {11, 14-Eicosatetraynoic Acid/pharmacology, 5, 8, Arachidonic Acid/*antagonists & inhibitors, Cell Differentiation/drug effects, Cell Division/drug effects, Cell Line, Cell Survival/drug effects, Cyclooxygenase Inhibitors/pharmacology, Humans, Indoles/pharmacology, Keratinocytes/cytology/*drug effects/*physiology, Lipoxygenase Inhibitors/pharmacology, Transformed, Umbelliferones/pharmacology},

pubstate = {published},

tppubtype = {article}

}