Anticarcinogenic effects of ursodeoxycholic acid in pancreatic adenocarcinoma cell models.

Changes to the composition of the microbiome in neoplasia, is termed oncobiosis, may affect tumor behavior through the changes to the secretion of bacterial metabolites. In this study we show, that ursodeoxycholic acid (UDCA), a bacterial metabolite, has cytostatic properties in pancreatic adenocarcinoma cell (PDAC) models. UDCA in concentrations corresponding to the human serum reference range suppressed PDAC cell proliferation.

Cytostatic Bacterial Metabolites Interfere with 5-Fluorouracil, Doxorubicin and Paclitaxel Efficiency in 4T1 Breast Cancer Cells.

The microbiome is capable of modulating the bioavailability of chemotherapy drugs, mainly due to metabolizing these agents. Multiple cytostatic bacterial metabolites were recently identified that have cytostatic effects on cancer cells. In this study, we addressed the question of whether a set of cytostatic bacterial metabolites (cadaverine, indolepropionic acid and indoxylsulfate) can interfere with the cytostatic effects of the chemotherapy agents used in the management of breast cancer (doxorubicin, gemcitabine, irinotecan, methotrexate, rucaparib, 5-fluorouracil and paclitaxel).

Radical collaboration during a global health emergency: development of the RDA COVID-19 data sharing recommendations and guidelines.

The coronavirus disease 2019 (COVID-19) global pandemic required a rapid and effective response. This included ethical and legally appropriate sharing of data. The European Commission (EC) called upon the Research Data Alliance (RDA) to recruit experts worldwide to quickly develop recommendations and guidelines for COVID-related data sharing.

Fostering global data sharing: highlighting the recommendations of the Research Data Alliance COVID-19 working group.

The systemic challenges of the COVID-19 pandemic require cross-disciplinary collaboration in a global and timely fashion. Such collaboration needs open research practices and the sharing of research outputs, such as data and code, thereby facilitating research and research reproducibility and timely collaboration beyond borders. The Research Data Alliance COVID-19 Working Group recently published a set of recommendations and guidelines on data sharing and related best practices for COVID-19 research.

Synthesis of (nor)tropeine (di)esters and allosteric modulation of glycine receptor binding.

(Hetero)aromatic mono- and diesters of tropine and nortropine were prepared. Modulation of [3H]strychnine binding to glycine receptors of rat spinal cord was examined with a ternary allosteric model. The esters displaced [3H]strychnine binding with nano- or micromolar potencies and strong negative cooperativity.

Hyperekplexia mutation R271L of alpha1 glycine receptors potentiates allosteric interactions of nortropeines, propofol and glycine with [3H]strychnine binding.

Human alpha1 and hyperekplexia mutant alpha1(R271L) glycine receptors (GlyRs) were transiently expressed in human embryonic kidney 293 cells for [3H]strychnine binding. Binding parameters were determined using a ternary allosteric model. The hyperekplexia mutation increased the positive cooperativity of 0.

Novel 17beta-substituted conformationally constrained neurosteroids that modulate GABA A receptors.

The goal of this study was to develop a series of allopregnanolone analogues substituted by conformationally constrained 17beta side chains to obtain additional information about the structure-activity relationship of 5alpha-reduced steroids to modulate GABA(A) receptors. Specifically, we introduced alkynyl-substituted 17beta side chains in which the triple bond is either directly attached to the 17beta-position or to the 21-position of the steroid skeleton. Furthermore, we investigated the effects of C22 and C20 modification.

Nanomolar allopregnanolone potentiates rat cerebellar GABAA receptors.

The ionophore function of gamma-aminobutyric acid A (GABA(A)) receptors was studied by whole-cell patch clamp electrophysiology in primary cultures of rat cerebellar cortex. Chloride currents elicited by 1 microM GABA were potentiated by allopregnanolone with a plateau of high affinity (EC(50) = 14 nM) and a peak of potentiation around 1 microM allopregnanolone. Furosemide (0.

High affinity, heterogeneous displacement of [3H]EBOB binding to cerebellar GABA A receptors by neurosteroids and GABA agonists.

Heterogeneous binding interactions of cerebellar GABA(A) receptors were investigated with GABA agonists and neurosteroids. GABA(A) receptors of rat cerebellum were labelled with [(3)H]ethynylbicycloorthobenzoate (EBOB), a convulsant radioligand. Saturation analysis revealed a homogenous, nanomolar population of [(3)H]EBOB binding.

Allosteric modulation of 5-HT3 serotonin receptors.

[(3)H]Granisetron binding to 5-HT(3) type serotonin receptors was examined in homogenates of rat forebrain and NG 108-15 cells. We have applied an allosteric model to 5-HT(3) receptor binding for the first time. Slope factors of displacement improved the modelling.

Synthesis of tropeines and allosteric modulation of ionotropic glycine receptors.

Twenty esters of 3 alpha- and 3beta-hydroxy(nor)tropanes and two amides of 3 alpha-aminotropane were prepared with substituted benzoic acids. These (nor)tropeines inhibited [(3)H]strychnine binding to glycine receptors in synaptosomal membranes of rat spinal cord. A ternary allosteric model was applied to determine the dissociation constants (K(A)) of the tropeines having strong negative cooperativities with [(3)H]strychnine binding (alpha > 10).

Allosteric modulation of glycine receptors is more efficacious for partial rather than full agonists.

Allosteric modulation of [3H]strychnine binding to glycine receptors (GlyRs) was examined in synaptosomal membranes of rat spinal cord. An allosteric model enabled us to determine the cooperativity factors of the allosteric agents with [3H]strychnine and glycine bindings (alpha and beta, respectively). We modified the allosteric model with a slope factor because the slope values of the displacement curves of partial agonists (beta-alanine, taurine and gamma-aminobutyric acid) were beyond unity.

Vinburnine decelerates [3H]N-methylscopolamine binding to recombinant human muscarinic M1-M4 acetylcholine receptors.

The kinetics of [3H]N-methylscopolamine binding to membranes of Chinese hamster ovary (CHO) cells expressing muscarinic M(1)-M(4) acetylcholine receptors was studied. [3H]N-methylscopolamine dissociation was used for the "single-point" analysis of allosteric modulation by vinburnine (L-eburnamonine). [3H]N-methylscopolamine dissociation was decelerated by vinburnine with EC(50) values of 29.

Dual cooperative allosteric modulation of binding to ionotropic glycine receptors.

Glycine receptors (GlyRs) were studied via [(3)H]strychnine binding to synaptosomal membranes of rat spinal cord. A ternary allosteric model was applied for the effects of tropeines, alcohols, minaxolone, nitrendipine, Zn(2+), muscarinic and serotonin receptor ligands. It enabled us to determine the dissociation constants of the allosteric agents (K(A)) and their cooperativity factors affecting the dissociation constants of [(3)H]strychnine (alphaK(S)) and glycine (betaK(L)).

Hyperekplexia mutation of glycine receptors: decreased gating efficacy with altered binding thermodynamics.

[(3)H]Strychnine binding was studied to recombinant human alpha(1) and the hyperekplexia mutant alpha(1)R271L glycine receptors (GlyRs) transiently expressed in human embryonic kidney (HEK)-293 cell cultures at 0, 18 and 37 degrees. The alpha(1)R271L mutation did not affect the linear van't Hoff plots of the exothermic binding of the antagonist [3H]strychnine while it turned taurine into an antagonist with exothermic binding. The inhibition constants of the agonist glycine showed opposite temperature dependence on alpha(1) GlyRs, corresponding to endothermic binding driven by large entropic increases.