Interaction of the antifungal ketoconazole and its diphenylphosphine derivatives with lipid bilayers: Insights into their antifungal action.

Ketoconazole (Ke) is an important antifungal drug, and two of its diphenylphosphinemethyl derivatives (KeP: PhPCH-Ke and KeOP: PhP(O)CH-Ke) have shown improved antifungal activity, namely against a yeast strain lacking ergosterol, suggesting alternative modes of action for azole compounds. In this context, the interactions of these compounds with a model of the cell membrane were investigated, using POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) large unilamellar vesicles and taking advantage of the intrinsic fluorescence of Ke, KeP and KeOP. Steady-state fluorescence spectra and anisotropy, including partition and aggregation studies, as well as fluorescence lifetime measurements, were carried out.

Unraveling environmental effects in the absorption and fluorescence spectra of p-methoxyphenylpiperazine derivatives.

The p-methoxyphenylpiperazine motif can be found in many biologically active molecules, including approved drugs. It is characterized by a relatively weak fluorescence, which can be employed in different types of studies involving molecules with this motif. In this work, a thorough analysis of the absorption, excitation and emission spectra of the diphenyl(aminomethyl)phosphine and tris(aminomethyl)phosphine derivatives of p-methoxyphenylpiperazine, supported by the DFT calculations (ωB97XD/6-311++G(d,p)) with NBO and QTAIM analysis also for different model molecules (e.

Evaluation of the Antiproliferative Properties of CpRu Complexes Containing N-Methylated Triazaphosphaadamantane Derivatives.

Piano-stool-{CpRu} complexes containing 1,3,5-triaza-7-phosphaadamantane (PTA), -methyl-1,3,5-triaza-7-phosphaadamantane (mPTA), and 3,7-dimethyl-1,3,7-triaza-5-phosphabyciclo[3.3.1]nonane (dmoPTA) were evaluated as drugs against breast cancer.

Hippocampal CA1 theta burst-induced LTP from weaning to adulthood: Cellular and molecular mechanisms in young male rats revisited.

Long-term potentiation (LTP) is a highly studied cellular process, yet determining the transduction and gamma aminobutyric acid (GABAergic) pathways that are the essential versus modulatory for LTP elicited by theta burst stimulation (TBS) in the hippocampal Cornu Ammonis 1 (CA1) area is still elusive, due to the use of different TBS intensities, patterns or different rodent/cellular models. We now characterised the developmental maturation and the transduction and GABAergic pathways required for mild TBS-induced LTP in hippocampal CA1 area in male rats. LTP induced by TBS (5x4) (five bursts of four pulses delivered at 100 Hz) lasted for up to 3 h and was increasingly larger from weaning to adulthood.

Sphingolipid-enriched domains in fungi.

Plasma membrane carries out multiple physiological functions that require its dynamic and tightly regulated organization into specialized domains of different size, stability, and lipid/protein composition. Sphingolipids are a group of lipids in which the plasma membrane is particularly enriched, thus being crucial for its structure and function. A specific type of sphingolipid-enriched plasma membrane domains, where ergosterol is depleted and lipids are tightly packed in a rigid gel phase, has recently been found in several fungal species, including yeasts and moulds.

Glucosylpolyphenols as Inhibitors of Aβ-Induced Fyn Kinase Activation and Tau Phosphorylation: Synthesis, Membrane Permeability, and Exploratory Target Assessment within the Scope of Type 2 Diabetes and Alzheimer's Disease.

Despite the rapidly increasing number of patients suffering from type 2 diabetes, Alzheimer's disease, and diabetes-induced dementia, there are no disease-modifying therapies that are able to prevent or block disease progress. In this work, we investigate the potential of nature-inspired glucosylpolyphenols against relevant targets, including islet amyloid polypeptide, glucosidases, and cholinesterases. Moreover, with the premise of Fyn kinase as a paradigm-shifting target in Alzheimer's drug discovery, we explore glucosylpolyphenols as blockers of Aβ-induced Fyn kinase activation while looking into downstream effects leading to Tau hyperphosphorylation.

Biophysical Analysis of Lipid Domains in Mammalian and Yeast Membranes by Fluorescence Spectroscopy.

The use of steady-state and time-resolved fluorescence spectroscopy to study sterol and sphingolipid-enriched lipid domains as diverse as the ones found in mammalian and fungal membranes is herein described. We first address how to prepare liposomes that mimic raft-containing membranes of mammalian cells and how to use fluorescence spectroscopy to characterize the biophysical properties of these membrane model systems. We further illustrate the application of Förster resonance energy transfer (FRET) to study nanodomain reorganization upon interaction with small bioactive molecules, phenolic acids, an important group of phytochemical compounds.

Liquid-Ordered Phase Formation by Mammalian and Yeast Sterols: A Common Feature With Organizational Differences.

Here, biophysical properties of membranes enriched in three metabolically related sterols are analyzed both and . Unlike cholesterol and ergosterol, the common metabolic precursor zymosterol is unable to induce the formation of a liquid ordered ( ) phase in model lipid membranes and can easily accommodate in a gel phase. As a result, Zym has a marginal ability to modulate the passive membrane permeability of lipid vesicles with different compositions, contrary to cholesterol and ergosterol.

Yeast Sphingolipid-Enriched Domains and Membrane Compartments in the Absence of Mannosyldiinositolphosphorylceramide.

The relevance of mannosyldiinositolphosphorylceramide [M(IP)C] synthesis, the terminal complex sphingolipid class in the yeast , for the lateral organization of the plasma membrane, and in particular for sphingolipid-enriched gel-like domains, was investigated by fluorescence spectroscopy and microscopy. We also addressed how changing the complex sphingolipid profile in the plasma membrane could influence the membrane compartments (MC) containing either the arginine/ H symporter Can1p (MCC) or the proton ATPase Pma1p (MCP). To achieve these goals, wild-type () and Δ cells, which are unable to synthesize M(IP)C accumulating mannosylinositolphosphorylceramide (MIPC), were compared.

Interaction with Blood Proteins of a Ruthenium(II) Nitrofuryl Semicarbazone Complex: Effect on the Antitumoral Activity.

The steady rise in the cancer burden and grim statistics set a vital need for new therapeutic solutions. Given their high efficiency, metallodrugs are quite appealing in cancer chemotherapy. This work examined the anticancer activity of an anti-trypanosomal ruthenium-based compound bearing the 5-nitrofuryl pharmacophore, [Ru(dmso)(5-nitro-2-furaldehyde semicarbazone)] (abbreviated as RuNTF; dmso is the dimethyl sulfoxide ligand).