1,721,002 research outputs found
Natural and Functionalized Molecules with Antioxidant and Scavenging Activity as Components of Innovative Lipid-based Artificial Tears
Full text linkLe principali forme farmaceutiche per uso oftalmico sono rappresentate dai colliri grazie alla loro semplicità di preparazione, sterilizzazione e somministrazione. Tuttavia, i colliri presentano una bassa biodisponibilità di circa il 5%. Ottimi risultati si sono ottenuti con l’utilizzo di sistemi di veicolazione di farmaci a base lipidica caratterizzati da elevata biocompatibilità. La nostra attenzione è stata rivolta all’utilizzo di due diverse molecole con potente potenziale antiossidante, l’Epigallocatechina-3-gallato (EGCG) e l’Edaravone, le quali hanno dimostrato la loro efficacia nel trattamento e/o prevenzione delle patologie oculari associate allo stress ossidativo. L’obbiettivo finale è lo sviluppo di un sistema di veicolazione di farmaci stabile ed efficiente considerando 3 punti fondamentali:
(a) Massimizzare la quantità di farmaco inglobata nel sistema di trasporto lipidico al fine aumentare la quantità di molecola che giunge al sito target. (
b) Stabilità colloidale e caratterizzazione dei sistemi di trasporto.
(c) Abilità di proteggere le cellule retinale dalla morte cellulare indotta dallo stress ossidativo.
Dai risultati ottenuti possiamo concludere che la percentuale di inglobamento della molecola EGCG risente dell’effetto salino e della composizione lipidica. In particolare, l’utilizzo di MgCl2 in combinazione con una matrice anionica ed, in presenza del Poloxamer-407, ci ha permesso di ottenere un sistema altamente stabile caratterizzato dal 100% di inglobamento. Questo sistema si è dimostrato capace di proteggere le cellule retinali dallo stress ossidativo in misura maggiore rispetto alla molecola veicolata tal quale. L’utilizzo di concentrazioni crescenti ci ha permesso di aumentare l’inglobamento dell’EGCG all’interno di fasi cubiche ed esagonali, altri sistemi di veicolazione di farmaci usati in campo oftalmico. La struttura di tutti i sistemi studiati è stata caratterizzata mediante esperimenti di diffrazione a raggi x e neutroni. Inoltre, l’introduzione di gruppi lipofili costituiti da catene di C-18, oltre a permettere il completo inglobamento delle molecole studiate, ha aumentato la loro capacità di proteggere le cellule retinale dalla morte indotta dallo stress ossidativo.This thesis presents an extended work concerning the development of lipid-based systems able to prevent and control the ocular diseases associated with oxidative stress. The eye drops dosage forms account for nearly 90% of currently available marketed formulations thanks of their simplicity, safety and acceptance by patients. However, the bioavailability of topically applied drugs is about 5%. The lipid-based nanocarriers, which are highly biocompatible, can carry the antioxidant to the specific site. Among the antioxidants used for ophthalmic applications, the attention was focused on Epigallocatechin-3-gallate and Edaravone molecules, which are well-known for being bioactive in ocular diseases associated with oxidative stress. Since the final aim was to create a stable and efficient delivery system, the design of lipid-based nanocarriers has been based on three critical targets:
a) High encapsulation efficiency in order to optimize the delivery of the active principle at the target sites.
b) Colloidal stability and characterization of lipid-based systems.
c) Ability to protect the retinal cells from oxidative stress-induced cell death.
From the obtained results, we concluded that the encapsulation percentage of EGCG inside liposomes showed specific ion effects together with influence of the lipid matrix composition. More in details, the combination of magnesium chloride, anionic matrix and Poloxamer-407 allow us to obtain a system highly stable with 100% EGCG encapsulation that was able to protect retinal cells from oxidative stress. Using increasing concentrations of EGCG we optimized the encapsulation efficiency of catechin inside the cubic and hexagonal phase, others interesting systems used in the ophthalmic field. The structures of all systems were characterized by X-Ray and Neutrons experiments. In addition, the introduction of lipophilic C-18 chain in EGCG and Edaravone molecules also increased their encapsulation efficiency inside a liposomal vector as well as their ability to protect the retinal cells from oxidative stress
Chemical Scaffolds for the Clinical Development of Mutant-Selective and Reversible Fourth-Generation EGFR-TKIs in NSCLC
Full text linkIn nonsmall cell lung cancer (NSCLC), as well as in other tumors, the targeted therapy is mainly represented by tyrosine kinase inhibitors (TKIs), small molecules able to target oncogenic driver alterations affecting the gene encoding the epidermal growth factor receptor (EGFR). Up to now, several different TKIs have been developed. However, cancer cells showed an incredible adaptive tumor response to the inhibition of the sequentially mutated EGFR (EGFRM+), triggering the need to explore novel pharmacochemical strategies. This Review summarizes the recent efforts in the development of new reversible next-generation EGFR TKIs to fight the resistance against T790M and C797S mutations. Specifically, after giving an overview of the role of the EGFR's signaling pathways in cancer progression, we are going to discuss the most relevant approved drugs and drug candidates in terms of chemical structure, binding modalities, and their potency and selectivity against the mutated EGFR over the wild-type form. This could provide important guidelines and rationale for the discovery and iterative development of new drugs
A combined EPR-molecular dynamics investigation of penetration of antioxidant lipid-based nitroxides in lipid bi-layer
No full textCholesterol-mediated oligomerization pathways of serotonin G-coupled receptor 5-HT2C
No full textSerotonin (5-HT) receptors have been shown to homodimerize and heterodimerize with other G protein-coupled receptors (GPCRs), although the details of this process have not yet been elucidated. Here we use coarse-grained molecular dynamics on monomeric 5-HT2C receptors to predict the transmembrane (TM) helices involved in such associations. All these simulations were carried out both in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayers and in mixed composition POPC-Cholesterol ones, to show whether the presence of cholesterol could directly influence and drive the dimeric association. The goal is to get insights on the self-assembly pathway leading to GPCRs 5-HT2C oligomerization, which is supposed to be the basis of its constitutional activity. From the analysis of the molecular dynamics trajectories, we observed the formation of 5-HT2C oligomers through self-assembly and we identified the main domains involved in the receptor dimerization. In particular, dimers and oligomers from the two different environments show TM4-TM5 and TM1-TM7-H8 as the preferential dimerization interfaces. Nevertheless, substantial differences arise for oligomers in POPC and in POPC-Chol membranes: in POPC-Chol the variability of dimers interfaces is strictly limited to the TM1-TM7-H8 and TM4-TM5 interfaces and the dimorphism depends on cholesterol that directly participates in its formation. These results are in agreement with both experimental evidences and other computational studies conducted on other GPCRs oligomerization
Tailoring the Barrier Properties of PLA: A State-of-the-Art Review for Food Packaging Applications
Full text linkIt is now well recognized that the production of petroleum-based packaging materials has created serious ecological problems for the environment due to their resistance to biodegradation. In this context, substantial research efforts have been made to promote the use of biodegradable films as sustainable alternatives to conventionally used packaging materials. Among several biopolymers, poly(lactide) (PLA) has found early application in the food industry thanks to its promising properties and is currently one of the most industrially produced bioplastics. However, more efforts are needed to enhance its performance and expand its applicability in this field, as packaging materials need to meet precise functional requirements such as suitable thermal, mechanical, and gas barrier properties. In particular, improving the mass transfer properties of materials to water vapor, oxygen, and/or carbon dioxide plays a very important role in maintaining food quality and safety, as the rate of typical food degradation reactions (i.e., oxidation, microbial development, and physical reactions) can be greatly reduced. Since most reviews dealing with the properties of PLA have mainly focused on strategies to improve its thermal and mechanical properties, this work aims to review relevant strategies to tailor the barrier properties of PLA-based materials, with the ultimate goal of providing a general guide for the design of PLA-based packaging materials with the desired mass transfer properties
Conformational Insight on WT- and Mutated-EGFR Receptor Activation and Inhibition by Epigallocatechin-3-Gallate: Over a Rational Basis for the Design of Selective Non-Small-Cell Lung Anticancer Agents
Full text linkNon-small cell lung cancer (NSCLC) represents a dicult condition to treat, due to
epidermal growth factor receptor (EGFR) kinase domain mutations, which lead to ligand-independent
phosphorylation. Deletion of five amino acids (ELREA) in exon 19 and mutational change from
leucine to arginine at position 858 (L858R) are responsible for tyrosine kinase domain aberrant
activation. These two common types of EGFR-mutated forms are clinically associated with high
response with Tyrosine Kinase Inhibitors (TKI); however, the secondary T790M mutation within
the Tyrosine Kinase Domain (TKD) determines a resistance to these EGFR-TKIs. Using molecular
dynamic simulation (MD), the present study investigated the architectural changes of wild-type
and mutants EGFR’s kinase domains in order to detect any conformational dierences that could
be associated with a constitutively activated state and thus to evaluate the dierences between the
wild-type and its mutated forms. In addition, in order to evaluate to which extent the EGFR mutations
aect its inhibition, Epigallocatechin 3-Gallate (EGCG) and Erlotinib (Erl), known EGFR-TKI, were
included in our study. Their binding modes with the EGFR-TK domain were elucidated and the
binding dierences between EGFR wild-type and the mutated forms were evidenced. The aminoacids
mutations directly influence the binding anity of these two inhibitors, resulting in a dierent ecacy
of Erl and EGCG inhibition. In particular, for the T790M/L858R EGFR, the binding modes of studied
inhibitors were compromised by aminoacidic substitution confirming the experimental findings.
These results may be useful for novel drug design strategies targeting the dimerization domain of the
EGFR mutated forms, thus preventing receptor activation
Side Effects of Curcumin: Epigenetic and Antiproliferative Implications for Normal Dermal Fibroblast and Breast Cancer Cells
Full text linkCurcumin is a yellow-orange pigment obtained from the plant Curcuma longa, which is known to exert beneficial effects in several diseases, including cancer. However, at high doses, it may produce toxic and carcinogenic effects in normal cells. In this context, we studied the effects of curcumin on normal human dermal fibroblast (HDF) cells and breast cancer cells (MCF7)
Investigation on the Synergy between Membrane Permeabilizing Amphiphilic α-Hydrazido Acids and Commonly Used Antibiotics against Drug-Resistant Bacteria
Full text linkThe growth of (multi)drug resistance in bacteria is among the most urgent global health issues. Monocationic amphiphilic α-hydrazido acid derivatives are structurally simple mimics of antimicrobial peptides (AMPs) with fewer drawbacks. Their mechanism of membrane permeabilization at subtoxic concentrations was found to begin with an initial electrostatic attraction of isolated amphiphile molecules to the phospholipid heads, followed by a rapid insertion of the apolar portions. As the accumulation into the bilayer proceeded, the membrane increased its fluidity and permeability without being subjected to major structural damage. After having ascertained that α-hydrazido acid amphiphiles do not interact with bacterial DNA, they were subjected to synergy evaluation for combinations with conventional antibiotics. Synergy was observed for combinations with tetracycline against sensitive S. aureus and E. coli, as well as with ciprofloxacin and colistin against resistant strains. Additivity with a remarkable recovery in activity of conventional antibiotics (from 2-fold to ≥32-fold) together with largely subtoxic concentrations of α-hydrazido acid derivatives was found for combinations with ciprofloxacin toward susceptible S. aureus and methicillin toward MRSa. However, no potentiation of conventional antibiotics was observed for combinations with linezolid and gentamicin against the corresponding resistant S. aureus and E. coli strains
Salts Influence Cathechins and Flavonoids Encapsulation in Liposomes: A Molecular Dynamics Investigation
No full textCathechins and flavonoids are responsible of numerous health benefits. Two of the most representatives' compounds for their antioxidant and therapeutic effects are Epigallocatechin 3-Gallate (EGCG), from green tea extracts, and morelloflavone (MF), from Garcinia dulcis. Here we explore, by atomistic Molecular Dynamics simulations, how EGCG and MF interact with lipid bilayers and we show the salts' influence on their encapsulation degree in neutral liposomes. As a result, we found out that EGCGs naturally bind to the hydrophilic regions of phospholipids, positioning themselves mostly at the interface between water and lipid phases. The presence of a salt clearly influences the EGCG molecules' absorption and the total effect depends strongly on the salt nature and concentration. Beside, for MF, we observed a high stability of the intermolecular MFs aggregates in water that strongly penalizes the flavonoid's interaction with the lipid polar heads. However, salts can influence MF's liposomal penetration, even if they are not able to promote completely its absorption inside the bilayer. For both compounds, the increase of penetration is more marked in presence of magnesium chloride, whilst calcium chloride showed the opposite effect. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Membrane composition allows the optimization of berberine encapsulation in liposomes
No full textBerberine (BBR) is a natural molecule with noteworthy pharmacological properties, including the prevention
of antibiotic resistance in Gram-negative bacteria. However, its oral bioavailability is poor, thus resulting in an impaired absorption and efficacy in humans. In combination with other drugs, liposomes have been shown to enhance the availability of the drug, representing a smart delivery system to target tissues and reduce negative side effects. To date, there is a lack of studies on BBR and liposomes that enable the rationalization and molecular-based design of such formulations for future use in humans. In this work, the encapsulation of BBR into liposomes is proposed to overcome current limitations using a combination of experimental and computational assays to rationalize the membrane composition of liposomes that maximizes BBR encapsulation. First, the encapsulation efficiency was measured for several membrane compositions, revealing that it is enhanced by cholesteryl hemisuccinate and, to a lesser extent, by cholesterol. The physical basis of the BBR encapsulation efficiency and permeability was clarified using molecular dynamics simulation: using the lipid composition, one can tune the capability of membranes to attract, i.e., to adsorb, the molecules onto their surface. Overall, these findings suggest a rational strategy to maximize the encapsulation efficiency of liposomes by using negatively charged lipids, thus representing the basis for designing delivery systems for BBR, useful to treat, e.g., antibiotic resistance
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