1,721,027 research outputs found
RATIONAL DESIGN OF FUNCTIONALIZED LIPIDS WITH ANTIOXIDANT AND SCAVENGING ACTIVITY AS COMPONENTS OF INNOVATIVE ARTIFICIAL TEARS
Get PDFDurante i tre anni di dottorato mi sono occupato del design razionale di lipidi funzionalizzati ad attività antiossidante da utilizzare per la formulazione di lacrime artificiali. Abbiamo scelto i liposomi per veicolare le molecole antiossidanti testate; siamo partiti utilizzando l’Edaravone (EDR), il quale è stato opportunamente funzionalizzato (EDR-C18), senza però diminuire le proprietà antiossidanti della molecola, quindi abbiamo condotto studi sperimentali evidenziando che l’EDR-C18 mantiene elevate capacità antiossidanti. Abbiamo condotto degli studi di simulazione di dinamica molecolare utilizzando un sistema lipidico puro contente POPC, e differenti concentrazioni di EDR-C18. I dati di simulazione hanno evidenziato una elevata stabilità dell’EDR-C18 in membrana. Abbiamo quindi determinato la concentrazione ottimale al fine di ottenere una intatta fluidità del sistema e allo stesso tempo una elevata quantità di antiossidante. Partendo da questo modello di simulazione, abbiamo creato altri sistemi di simulazione in cui abbiam investigato l’effetto dei Sali. Abbiamo testato soluzioni saline già comunemente utilizzate nella formulazione di lacrime artificiali, ed abbiamo riscontrato nel CaCl2 il sale maggiormente utile per la nostra strategia. Tali sistemi sono estremamente promettenti per la formulazione di gocce oculari. Un’altra molecola testata è l’epigallocatechin3-Gallato (EGCG). Essa ha la capacità di interagire spontaneamente con sistemi lipidici, perciò non è stata funzionalizzata. Abbiamo condotto delle simulazioni di dinamica molecolare creando sistemi lipidici misti per indagare l’effetto della matrice sulla capacità di inglobamento dell’EGCG. Abbiamo poi modulato sulla concentrazione salina ed abbiamo individuato nel sistema lipidico anionico con una quantità di Magnesio pari a 5:1 in rapporto molare con EGCG, il sistema in cui tutto l’EGCG introdotto viene inglobato, aumentando la biodisponibilità della molecola al massimo possibile
Chemical Scaffolds for the Clinical Development of Mutant-Selective and Reversible Fourth-Generation EGFR-TKIs in NSCLC
Get PDFIn 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
Get PDFIt 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
Get PDFNon-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
Get PDFCurcumin 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
Get PDFThe 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
Mechanisms behind pyrethroid toxicity: involvement of epigenetic impairment in a progressive model of neurodegeneration induced by neonatal pesticide exposure.
No full textNeonatal exposure to low dosage of permethrin (PERM) pesticide during brain development leads to the impairment of the dopaminergic system in rat striatum nucleus, promoting oxidative stress and behavioral changes associated, later in life, with the development of a progressive Parkinson's-like disease (PD).
Previous studies demonstrated that PERM, a widely used pesticide suitable for pest control and anti-woodworm agent, is able to modulate DNA methyltransferases and -synuclein expression by NURR1 modulation in early life exposed rats. Data obtained in this work suggested that epigenetics could be a potential mechanism through which environmental factors interact with the genome by modulating gene expression. This hypothesis was supported by the evidence that the progressive PD could be developed in sensitive animals only if the exposure take place during the early window of epigenetic plasticity.
This study aimed us to evaluate if PERM could modulate global DNA methylation and hydroxymethylation, as well as histone post-translational modifications, at specific gene loci in the early stages of disease progression. Moreover, in order to investigate PERM/Nurr1 and α-synuclein/NURR1 interactions, in silico studies were performed and compared with known Nurr1 agonists’ binding association and other biological data obtained in the rat model.
Results show significant alteration in epigenetic regulatory mechanisms and dopamine-related gene expression. Additionally, we found that PERM competes for the same two binding sites of known NURR1 agonists, with a lower free energy of binding for PERM, suggesting a stable association of PERM with the orphan receptor. A strong affinity for NURR1 by synuclein was also identified.
This study links the risk in the onset of a late neurodegeneration process with an early exposure to an environmental pesticide. The control of xenobiotic exposure during the epigenetic window of plasticity might be useful to preserve health in sensitive organisms
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