Exploring the physicochemical properties of the integration of Tristearoyl uridine in Langmuir monolayers: An approach to cell membrane modeling for prodrugs.

Understanding the mechanisms by which drugs interact with cell membranes is crucial for unraveling the underlying biochemical and biophysical processes that occur on the surface of these membranes. Our research focused on studying the interaction between an ester-type derivative of tristearoyl uridine and model cell membranes composed of lipid monolayers at the air-water interface. For that, we selected a specific lipid to simulate nontumorigenic cell membranes, namely 1,2-dihexadecanoyl-sn-glycero-3-phospho-l-serine. We noted significant changes in the surface pressure-area isotherms, with a noticeable shift towards larger areas, which was lower than expected for ideal mixtures, indicating monolayer condensation. Furthermore, the viscoelastic properties of the interfacial film demonstrated an increase in both the elastic and viscous parameters for the mixed film. We also observed structural alterations using vibrational spectroscopy, which revealed an increase in the all-trans to gauche conformers ratio. This confirmed the stiffening effect of the prodrug on the lipid monolayer. In summary, this study indicates that this lipophilic prodrug significantly impacts the lipid monolayer's thermodynamic, rheological, electrical, and molecular characteristics. This information is crucial for understanding how the drug interacts with specific sites on the cellular membrane. It also has implications for drug delivery, as the drug's passage into the cytosol may involve traversing the lipid bilayer.

A Thermodynamic Study on the Interaction between RH-23 Peptide and DMPC-Based Biomembrane Models.

Investigation of the interaction between drugs and biomembrane models, as a strategy to study and eventually improve drug/substrate interactions, is a crucial factor in preliminary screening. Synthesized peptides represent a source of potential anticancer and theragnostic drugs. In this study, we investigated the interaction of a novel synthesized peptide, called RH-23, with a simplified dimyristoylphosphatidylcholine (DMPC) model of the cellular membrane. The interaction of RH-23 with DMPC, organized either in multilamellar vesicles (MLVs) and in Langmuir-Blodgett (LB) monolayers, was assessed using thermodynamic techniques, namely differential scanning calorimetry (DSC) and LB. The calorimetric evaluations showed that RH-23 inserted into MLVs, causing a stabilization of the phospholipid gel phase that increased with the molar fraction of RH-23. Interplay with LB monolayers revealed that RH-23 interacted with DMPC molecules. This work represents the first experimental thermodynamic study on the interaction between RH-23 and a simplified model of the lipid membrane, thus providing a basis for further evaluations of the effect of RH-23 on biological membranes and its therapeutic/diagnostic potential.

Interaction of Lipophilic Cytarabine Derivatives with Biomembrane Model at the Air/Water Interface.

Cell membrane models are useful for obtaining molecular-level information on the interaction of biologically active molecules whose activity is believed to depend also on their effects on the membrane. Cytarabine was conjugated with fatty acids to improve the drug lipophilicity and the interaction with the biomembrane model. Cytarabine was conjugated with fatty acids of different lengths to form the trimyristoyl cytarabine and the tristearoyl cytarabine derivatives. Their interaction with biomembrane models constituted by dimyristoylphosphatidylcholine (DMPC) monolayers was studied by employing the Langmuir-Blodgett technique. DMPC/cytarabine, DMPC/trimyristoyl cytarabine and DMPC/tristearoyl cytarabine mixed monolayers at increasing molar fractions of the compound were prepared and placed on the subphase. The mean molecular area/surface pressure isotherms were recorded at 37 °C. Between the molecules of DMPC and those of cytarabine or prodrugs, repulsive forces act. However, these forces are very weak between DMPC and cytarabine and stronger between DMPC and the cytarabine derivatives, thus avoiding the expulsion of the compounds at higher surface pressure and modifying the stability of the mixed monolayer. The fatty acid moieties could then modulate the affinity of cytarabine for biomembranes.

Insecticidal Activity of Four Essential Oils Extracted from Chilean Patagonian Plants as Potential Organic Pesticides.

Patagonia is a geographical area characterized by a wide plant biodiversity. Several native plant species are traditionally used in medicine by the local population and demonstrated to be sources of biologically active compounds. Due to the massive need for green and sustainable pesticides, this study was conducted to evaluate the insecticidal activity of essential oils (EOs) from understudied plants growing in this propitious area. Ciprés (Pilgerodendron uviferum), tepa (Laureliopsis philippiana), canelo (Drimys winteri), and paramela (Adesmia boronioides) EOs were extracted through steam distillation, and their compositions were analyzed through GC−MS analysis. EO contact toxicity against Musca domestica L., Spodoptera littoralis (Boisd.), and Culex quinquefasciatus Say was then evaluated. As a general trend, EOs performed better on housefly males over females. Ciprés EO showed the highest insecticidal efficacy. The LD50(90) values were 68.6 (183.7) and 11.3 (75.1) µg adult−1 on housefly females and males, respectively. All EOs were effective against S. littoralis larvae; LD50 values were 33.2−66.7 µg larva−1, and tepa EO was the most effective in terms of LD90 (i.e., <100 µg larva−1). Canelo, tepa, and paramela EOs were highly effective on C. quinquefasciatus larvae, with LC50 values < 100 µL L−1. Again, tepa EO achieved LD90 < 100 µL L−1. This EO was characterized by safrole (43.1%), linalool (27.9%), and methyl eugenol (6.9%) as major constituents. Overall, Patagonian native plant EOs can represent a valid resource for local stakeholders, to develop effective insecticides for pest and vector management, pending a proper focus on their formulation and nontarget effects.

A Langmuir-Blodgett Study of the Interaction between Amphotericin B and Lipids of Histoplasma capsulatum.

Histoplasma capsulatum is a dimorphic, thermal, and nutritional fungus. In the environment and at an average temperature of 28 °C, it develops as a mold that is composed of infecting particles. Once in the host or in cultures at 37 °C, it undergoes a transition into the parasitic form. In the present work, we performed chemical extraction and characterization using chromatography techniques of the associated lipid composition of the external surface of the cell wall of the mycelial phase of two isolates of the H. capsulatum: one clinical and one environmental. Several differences were evidenced in the fatty acids in the phospholipid composition. Surface pressure-area isotherms and compression module curves of the Amphotericin B and lipid extract monolayers, as well as (AmB)-lipid extract mixed monolayers were recorded. Results show a high affinity of AmB towards lipid extracts. The most stable monolayers were formed by AmB + environmental with a mass ratio of 1:3 and AmB + clinical with a mass ratio of 1:2. Knowledge of the AmB aggregation processes at a molecular level and the characterization of the lipid extracts allows the possibility to understand the interaction between the AmB and the lipid fractions of H. capsulatum.

Molecular Information on the Potential of Europium Complexes for Local Recognition of a Nucleoside-Based Drug by Using Nanostructured Interfaces Assembled as Langmuir-Blodgett Films.

The production of nanostructured materials for biological and medical applications may be applied toward the conjugation of adequate substances to boost the stimulus response of sensors and diagnostic probes. In this sense, Langmuir-Blodgett films constituted of bioinspired and biomimetic materials have attracted attention because of the ease of manipulation of the molecular architecture. In this paper, we employed a nucleoside-based drug, which was linked with a sterol hydrophobic moiety (3',4'-acetonide-uridine-succinate-cholesterol conjugate) to provide it an amphiphilic character. The drug was spread on the air-water interface, alone or mixed with stearic acid, forming Langmuir monolayers, and the complex Eu(tta)3(H2O)2 was incorporated in the drug-containing monolayer. Interactions at the air-water interface between stearic acid, the drug, and the europium complex were then investigated with tensiometry, surface potential, infrared spectroscopy, and Brewster angle microscopy. The Langmuir films were transferred to solid supports as Langmuir-Blodgett films, which presented luminescent properties that could be tuned according to the molecular architecture. We believe that these results can serve as a novel approach to characterize and assemble materials organized in the molecular scale for medical applications.

Antifungal activity of Mongolian medicinal plant extracts.

The in vitro antifungal activity of extracts obtained from 14 medicinal plants of the mongolian flora were investigated by measuring their minimal inhibitory concentration (MIC) against fungi cause of cutaneous diseases such as Candida species, dermatophytes and Malassezia furfur. Among the species examined, Stellaria dichotoma L., Scutellaria scordifolia L. Aquilegia sibirica Fisch. Et Schrenk. and Hyoscyamus niger L. extracts demonstrated antifungal activity against all studied fungi. In particular, S. scordifolia L. methanol extract, obtained at room temperature, showed the best activity against Candida spp., Malassezia furfur and dermatophytes with GMMIC50 values of 22 µg/mL, 64 µg/mL and 32 µg/mL, respectively. The flavones, luteolin and apigenin, identified in S. scordifolia extracts, and rutin identified in S. dichotoma and Hyoscyamus niger L. extracts, could be responsible of the observed antifungal activity.

Anomalous interaction of tri-acyl ester derivatives of uridine nucleoside with a l-α-dimyristoylphosphatidylcholine biomembrane model: a differential scanning calorimetry study.

OBJECTIVES: Uridine was conjugated with fatty acids to improve the drug lipophilicity and the interaction with phospholipid bilayers. METHODS: The esterification reaction using carbodiimides compounds as coupling agents and a nucleophilic catalyst allowed us to synthesize tri-acyl ester derivatives of uridine with fatty acids. Analysis of molecular interactions between these tri-acyl ester derivatives and l-α-dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV) - as a mammalian cell membrane model - have been performed by differential scanning calorimetry (DSC). KEY FINDINGS: The DSC thermograms suggest that nucleoside and uridine triacetate softly interact with phospholipidic multilamellar vesicles which are predominantly located between the polar phase, whereas the tri-acyl ester derivatives with fatty acids (myristic and stearic acids) present a strongly interaction with the DMPC bilayer due to the nucleoside and aliphatic chains parts which are oriented towards the polar and lipophilic phases of the phospholipidic bilayer, respectively. However, the effects caused by the tri-myristoyl uridine and tri-stearoyl uridine are different. CONCLUSIONS: We show how the structural changes of uridine modulate the calorimetric behaviour of DMPC shedding light on their affinity with the phospholipidic biomembrane model.

Simulation of the song motor pathway in birds: A single neuron initiates a chain of events that produces birdsong with realistic spectra properties.

Birdsong is a complex learned behavior regulated by Neuromuscular coordination of different muscle sets necessary for producing relevant sounds. We developed a heterogeneous and stochastically connected neural network representing the pathway from the high vocal center (HVC) to the robust nucleus of the arcopallium (RA) neurons that drive the muscles to generate sounds. We show that a single active neuron is sufficient to initiate a chain of spiking events that results to excite the entire network system. The network could synthesize realistic bird sounds spectra, with spontaneous generation of intermittent sound bursts typical of birdsong (song syllables). This study confirms experiments on animals and on humans, where results have shown that single neurons are responsible for the activation of complex behavior or are associated with high-level perception events.

Synthesis and interaction of sterol-uridine conjugate with DMPC liposomes studied by differential scanning calorimetry.

Differential scanning calorimetry (DSC) is a thermoanalytical technique which provides information on the interaction between drugs and models of cell membranes. Studies on the calorimetric behavior of hydrated phospholipids within liposomes are employed to shed light on the changes in the physico-chemical properties when interacting with drugs. In this report, new potential anti-cancer drugs such as uridine and uridine derivatives (acetonide and its succinate), 3ß-5α,8α-endoperoxide-cholestan-6-en-3-ol (5,8-epidioxicholesterol) and conjugate (uridine acetonide-epidioxicholesterol succinate) have been synthesized. Steglich esterification method using coupling agents allowed to obtain the uridine acetonide-sterol conjugate. The study on the interaction between the drugs and dimiristoyl-phophatidilcholine (DMPC) liposomes has been conducted by the use of DSC. The analysis of the DSC curves indicated that the uridine and derivatives (acetonide and its succinate) present a very soft interaction with the DMPC liposomes, whereas the 5,8-epidioxicholesterol and the conjugate showed a strong effect on the thermotropic behavior. Our results suggested that the lipophilic character of uridine acetonide-sterol conjugate improves the affinity with the DMPC liposomes.