Design of New Schiff Bases and Their Heavy Metal Ion Complexes for Environmental Applications: A Molecular Dynamics and Density Function Theory Study.

Schiff bases (SBs) are important ligands in coordination chemistry due to their unique structural properties. Their ability to form complexes with metal ions has been exploited for the environmental detection of emerging water contaminants. In this work, we evaluated the complexation ability of three newly proposed SBs, 1-3, by complete conformational analysis, using a combination of Molecular Dynamics and Density Functional Theory studies, to understand their ability to coordinate toxic heavy metal (HMs) ions. From this study, it emerges that all the ligands present geometries that make them suitable to complex HMs through the N-imino moieties or, in the case of 3, with the support of the oxygen atoms of the ethylene diether chain. In particular, this ligand shows the most promising coordination behavior, particularly with Pb2+.

Density Functional Theory Calculations: A Useful Tool to Investigate Mechanisms of 1,3-Dipolar Cycloaddition Reactions.

The present review contains a representative sampling of mechanistic studies, which have appeared in the literature in the last 5 years, on 1,3-dipolar cycloaddition reactions, using DFT calculations. Attention is focused on the mechanistic insights into 1,3-dipoles of propargyl/allenyl type and allyl type such as aza-ylides, nitrile oxides and azomethyne ylides and nitrones, respectively. The important role played by various metal-chiral-ligand complexes and the use of chiral eductors in promoting the site-, regio-, diastereo- and enatioselectivity of the reaction are also outlined.

Palladium Iodide Catalyzed Multicomponent Carbonylative Synthesis of 2-(4-Acylfuran-2-yl)acetamides.

2-Propargyl-1,3-dicarbonyl compounds have been carbonylated under oxidative conditions and with the catalysis of the PdI2/KI catalytic system to selectively afford previously unreported 2-(4-acylfuran-2-yl)acetamides in fair to good yields (54-81%) over 19 examples. The process takes place under relatively mild conditions and occurs via a mechanistic pathway involving Csp-H activation by oxidative monoamincarbonylation of the terminal triple bond of the substrates with formation of 2-ynamide intermediates, followed by 5-exo-dig O-cyclization (via intramolecular conjugate addition of the in situ formed enolate to the 2-ynamide moiety) and aromative isomerization.

Antiviral Compounds to Address Influenza Pandemics: An Update from 2016-2022.

In recent decades, the world has gained experience of the dangerous effects of pandemic events caused by emerging respiratory viruses. In particular, annual epidemics of influenza are responsible for severe illness and deaths. Even if conventional influenza vaccines represent the most effective tool for preventing virus infections, they are not completely effective in patients with severe chronic disease and immunocompromised and new small molecules have emerged to prevent and control the influenza viruses. Thus, the attention of chemists is continuously focused on the synthesis of new antiviral drugs able to interact with the different molecular targets involved in the virus replication cycle. To date, different classes of influenza viruses inhibitors able to target neuraminidase enzyme, hemagglutinin protein, Matrix-2 (M2) protein ion channel, nucleoprotein or RNA-dependent RNA polymerase have been synthesized using several synthetic strategies comprising the chemical modification of currently used drugs. The best results, in terms of inhibitory activity, are in the nanomolar range and have been obtained from the chemical modification of clinically used drugs such as Peramivir, Zanamivir, Oseltamir, Rimantadine, as well as sialylated molecules, and hydroxypyridinone derivatives. The aim of this review is to report, covering the period 2016-2022, the most recent routes related to the synthesis of effective influenza virus inhibitors.

Moving forward through the in silico modeling of multiple sclerosis: Treatment layer implementation and validation.

Multiple sclerosis is an autoimmune inflammatory disease that affects the central nervous system through chronic demyelination and loss of oligodendrocytes. Since the relapsing-remitting form is the most prevalent, relapse-reducing therapies are a primary choice for specialists. Universal Immune System Simulator is an agent-based model that simulates the human immune system dynamics under physiological conditions and during several diseases, including multiple sclerosis. In this work, we extended the UISS-MS disease layer by adding two new treatments, i.e., cladribine and ocrelizumab, to show that UISS-MS can be potentially used to predict the effects of any existing or newly designed treatment against multiple sclerosis. To retrospectively validate UISS-MS with ocrelizumab and cladribine, we extracted the clinical and MRI data from patients included in two clinical trials, thus creating specific cohorts of digital patients for predicting and validating the effects of the considered drugs. The obtained results mirror those of the clinical trials, demonstrating that UISS-MS can correctly simulate the mechanisms of action and outcomes of the treatments. The successful retrospective validation concurred to confirm that UISS-MS can be considered a digital twin solution to be used as a support system to inform clinical decisions and predict disease course and therapeutic response at a single patient level.

Development of AMBER Parameters for Molecular Simulations of Selected Boron-Based Covalent Ligands.

Boron containing compounds (BCCs) aroused increasing interest in the scientific community due to their wide application as drugs in various fields. In order to design new compounds hopefully endowed with pharmacological activity and also investigate their conformational behavior, the support of computational studies is crucial. Nevertheless, the suitable molecular mechanics parameterization and the force fields needed to perform these simulations are not completely available for this class of molecules. In this paper, Amber force field parameters for phenyl-, benzyl-, benzylamino-, and methylamino-boronates, a group of boron-containing compounds involved in different branches of the medicinal chemistry, were created. The robustness of the obtained data was confirmed through molecular dynamics simulations on ligand/ß-lactamases covalent complexes. The ligand torsional angles, populated over the trajectory frames, were confirmed by values found in the ligand geometries, located through optimizations at the DFT/B3LYP/6-31g(d) level, using water as a solvent. In summary, this study successfully provided a library of parameters, opening the possibility to perform molecular dynamics simulations of this class of boron-containing compounds.

Chitosan/POSS Hybrid Hydrogels for Bone Tissue Engineering.

Hybrid hydrogels composed of chitosan (CS) have shown great potential in bone tissue engineering and regeneration. The introduction of polyhedral oligomeric silsesquioxanes (POSS) in the biopolymeric matrix has been demonstrated to improve the rheological and biological properties of the hybrid composites. In this work, we have integrated the favourable features of chitosan (CS) and POSS nanoparticles to design new nanocomposites for bone tissue regeneration, focusing our attention on the effect of POSS concentration within the CS matrix (0.5, 1, and 1.5 equivalents in weight of POSS with respect to CS) on the chemical, physical, rheological, and in vitro biological properties of the final composites. The drug release ability of the synthesized hydrogel scaffolds were also investigated using, as the model drug, ketoprofen, that was included in the scaffold during the gelling procedure, showing a more controlled release for the hybrids with respect to CS (86-91% of drug released after two weeks). The results of the in vitro biological tests performed on human fetal osteoblastic cells (hFOB 1.19) culture demonstrated the great biocompatibility of the hybrid materials. The hybrids, at the different POSS concentrations, showed values of cell mortality superimposable with control cells (11.1 vs. 9.8%), thus revealing the CS/POSS hydrogels as possible candidates for bone tissue engineering applications.

Chemoselective Oxidation of Isoxazolidines with Ruthenium Tetroxide: A Successful Intertwining of Combined Theoretical and Experimental Data.

The direct oxidation reaction of isoxazolidines plays an important role in organic chemistry, leading to the synthesis of biologically active compounds. In this paper, we report a computational mechanistic study of RuO4-catalyzed oxidation of differently N-substituted isoxazolidines 1a-c. Attention was focused on the endo/exo oxidation selectivity. For all the investigated compounds, the exo attack is preferred to the endo one, showing exo percentages growing in parallel with the stability order of transient carbocations found along the reaction pathway. The study has been supported by experimental data that nicely confirm the modeling results.

Manejo de las fracturas maxilofaciales y sus complicaciones / Management of maxillofacial fractures and its complications

RESUMEN Antecedentes: el trauma maxilofacial corresponde a toda lesión traumática del macizo facial. Actualmente representa uno de los problemas de salud más importantes en el mundo. Nuestro objetivo es realizar un análisis de nuestra experiencia en las intervenciones realizadas en pacientes internados y sus complicaciones. Material y métodos: se realizó un estudio descriptivo, retrospectivo y observacional de 205 pacientes con fracturas maxilofaciales desde el año 2011 hasta el año 2019. Resultados: el 81,46% fueron hombres (n: 167) y el rango etario más afectado osciló entre los 21 y 30 años con el 38,54% (n:79). El accidente de tránsito 56,1% (n:115) fue el mecanismo de trauma más frecuente. Los tipos de fracturas faciales fueron: panfaciales 12,2% (n: 25), tercio superior 1,46% (n:3), tercio medio 72,2% (n:148) y tercio inferior 14,15% (n:29). Dentro del tercio superior, el 66,67% (n:2) fueron fracturas del seno frontal asociadas al hueso frontal, en el tercio medio las combinadas en un 54,73% (n:81) y en el tercio inferior, las complejas en el 34,48% (n:10). Fueron intervenidos 199 pacientes (97,07%). Solo el 11,56% (n:23) presentó alguna complicación. No se observaron complicaciones graves. Discusión: según nuestra serie, la mayoría de los pacientes fueron hombres jóvenes; la causa más frecuente, el accidente de tránsito, y el tercio medio, el más afectado, resultados estos similares a los de otros estudios publicados. El tratamiento quirúrgico fue principalmente reducción abierta y fijación con material de osteosíntesis de titanio, un procedimiento seguro y fiable, que permite restablecer la funcionalidad previa al traumatismo, con un índice muy bajo de complicaciones posoperatorias.

ABSTRACT Background: Maxillofacial trauma corresponds to all traumatic injuries affecting the facial bones. Nowadays, it represents one of the main healthcare issues worldwide. The aim of this study is to analyze our experience in the interventions performed in hospitalized and their complications. Material and methods: We performed a retrospective and observational study of 205 patients with maxillofacial fractures from 2011 to 2019. Results: 81.46% were men (n = 167) and 38.54% (n = 79) of the patients were between 21 and 30 years of age. Traffic collision was the most common mechanism of trauma (56,1%, n = 115). The types of facial fractures were panfacial (12.2%; n = 25), of the upper-third (1.43%; n = 3), of the middle-third (72.2%; n = 148) and of the lower third (14.15%; n = 29). In the upper third of the face frontal sinus fractures associated with the frontal bone were the most common (66.67%; n =2); in the middle-third combined fractures were most prevalent (54.73%; n = 81) while complex fractures were most frequent in the lower third (34,48%; n = 10). One-hundred and ninety-one patients were operated on (97.07%). Complications occurred in only 11.56% (n = 23) and were not serious. Discusion: In our series, most patients were young men, traffic collisions were the most common cause of trauma, and the middle third of the face was the most affected region. These results are similar to our publications. Surgical management, mostly by open reduction and fixation with titanium-based osteosynthesis material, is an effective, safe and reliable procedure, which allows the restoration of pre-trauma function, with very low rate of postoperative complications.

The Effect of Weaning with Adult Food Typical of the Mediterranean Diet on Taste Development and Eating Habits of Children: A Randomized Trial.

Mediterranean Diet (Med Diet) is one of the healthiest dietary patterns. We aimed to verify the effects of weaning (i.e., the introduction of solid foods in infants previously fed only with milk) using adult foods typical of Med Diet on children eating habits, and on the microbiota composition. A randomized controlled clinical trial on 394 healthy infants randomized in a 1:1 ratio in a Med Diet group weaned with fresh; seasonal and tasty foods of Med Diet and control group predominantly weaned with industrial baby foods. The primary end point was the percentage of children showing a good adherence to Med Diet at 36 months. Secondary end points were mother's changes in adherence to Med Diet and differences in children gut microbiota. At 36 months, children showing a good adherence to Med Diet were 59.3% in the Med Diet group and 34.3% in the control group (p < 0.001). An increase in adherence to the Med Diet was observed in the mothers of the Med Diet group children (p < 0.001). At 4 years of age children in the Med Diet group had a higher gut microbial diversity and a higher abundance of beneficial taxa. A Mediterranean weaning with adult food may become a strategy for early nutritional education, to develop a healthy microbiota, to prevent inflammatory chronic diseases and to ameliorate eating habits in children and their families.

On the size, shape and energetics of the hydration shell around alkanes.

A large number of clathrate-like cages have been proposed as the very first hydration shell of alkanes. The cages include canonical structures commonly found in clathrate hydrates and many others, not previously reported, derived from the carbon fullerene cavities. These structures have a rich and variegated form, which can adapt to the shape and conformation of the solute. They avoid "wasting" hydrogen bonds, while minimizing the volume cage and maximizing the solute-solvent van der Waals interactions. DFT/M06-2X and MP2 ab initio calculations give comparable structural and energetic results although the latter predicts slightly larger cages for a given solute. It is shown that the van der Waals interactions are substantial and the large exoenergetic values found for isobutane and cyclopentane provide an explanation for the surprising high melting points of related hydrates at room pressure. The encaging enthalpy for various hydrocarbons is similar to the enthalpy of solution measured at a temperature just above the melting point of aqueous hydrocarbon solutions, thus indicating that water molecules should not deviate too much from the configuration with O-H bonds tangentially oriented with respect to the solute surface. The computed trend differs from the enthalpy of solution measured at room temperature, thus the very first hydration shell departs, up to a certain degree, from the clathrate-like structures.

Synthesis and Biological Evaluation of 2,3,4-Triaryl-1,2,4-oxadiazol-5-ones as p38 MAPK Inhibitors.

A series of azastilbene derivatives, characterized by the presence of the 1,2,4-oxadiazole-5-one system as a linker of the two aromatic rings of stilbenes, have been prepared as novel potential inhibitors of p38 MAPK. Biological assays indicated that some of the synthesized compounds are endowed with good inhibitory activity towards the kinase. Molecular modeling data support the biological results showing that the designed compounds possess a reasonable binding mode in the ATP binding pocket of p38α kinase with a good binding affinity.

Amyloid-Beta Induces Different Expression Pattern of Tissue Transglutaminase and Its Isoforms on Olfactory Ensheathing Cells: Modulatory Effect of Indicaxanthin.

Herein, we assessed the effect of full native peptide of amyloid-beta (Aß) (1-42) and its fragments (25-35 and 35-25) on tissue transglutaminase (TG2) and its isoforms (TG2-Long and TG2-Short) expression levels on olfactory ensheathing cells (OECs). Vimentin and glial fibrillary acid protein (GFAP) were also studied. The effect of the pre-treatment with indicaxanthin from Opuntia ficus-indica fruit on TG2 expression levels and its isoforms, cell viability, total reactive oxygen species (ROS), superoxide anion (O2-), and apoptotic pathway activation was assessed. The levels of Nestin and cyclin D1 were also evaluated. Our findings highlight that OECs exposure to Aß(1-42) and its fragments induced an increase in TG2 expression levels and a different expression pattern of its isoforms. Indicaxanthin pre-treatment reduced TG2 overexpression, modulating the expression of TG2 isoforms. It reduced total ROS and O2- production, GFAP and Vimentin levels, inhibiting apoptotic pathway activation. It also induced an increase in the Nestin and cyclin D1 expression levels. Our data demonstrated that indicaxanthin pre-treatment stimulated OECs self-renewal through the reparative activity played by TG2. They also suggest that Aß might modify TG2 conformation in OECs and that indicaxanthin pre-treatment might modulate TG2 conformation, stimulating neural regeneration in Alzheimer's disease.

A Zinc-Mediated Deprotective Annulation Approach to New Polycyclic Heterocycles.

A straightforward approach to new polycyclic heterocycles, 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-ones, is presented. It is based on the ZnCl2-promoted deprotective 6-endo-dig heterocyclization of N-Boc-2-alkynylbenzimidazoles under mild conditions (CH2Cl2, 40 °C for 3 h). The zinc center plays a dual role, as it promotes Boc deprotection (with formation of the tert-butyl carbocation, which can be trapped by substrates bearing a nucleophilic group) and activates the triple bond toward intramolecular nucleophilic attack by the carbamate group. The structure of representative products has been confirmed by X-ray diffraction analysis.

Gene Silencing of Transferrin-1 Receptor as a Potential Therapeutic Target for Human Follicular and Anaplastic Thyroid Cancer.

Herein, we assess the gene expression changes activated in thyroid tumors through a computational approach, using the MapReduce algorithm. Through this predictive analysis, we identified the TfR1 gene as a critical mediator of thyroid tumor progression. Then, we investigated the effect of TfR1 gene silencing through small interfering RNA (siRNA) in the expression of extracellular signal-regulated kinase 1/2 (Erk1/2) pathway and c-Myc in human differentiated follicular and undifferentiated anaplastic thyroid cancer. The expression levels of cyclin D1, p53, and p27, proteins involved in cell cycle progression, were also evaluated. The effect of TfR1 gene silencing through siRNA on the apoptotic pathway activation was also tested. Computational prediction and in vitro studies demonstrate that TfR1 plays a key role in thyroid cancer and that its downregulation was able to inhibit the ERK pathway, reducing also c-Myc expression, which blocks the cell cycle and activates the apoptotic pathway. We demonstrate that TfR1 plays a crucial role for a rapid and transient activation of the ERK signaling pathway, which induces a deregulation of genes involved in the aberrant accumulation of intracellular free iron and in drug resistance. We also suggest that TfR1 might represent an important target for thyroid cancer therapy.

Functionalized polyhedral oligosilsesquioxane (POSS) based composites for bone tissue engineering: synthesis, computational and biological studies.

Functionalized polyhedral oligosilsesquioxanes (POSS) containing an isoxazolidine nucleus have been synthesized by microwave assisted 1,3-dipolar cycloaddition of N-methyl-C-alkoxycarbonyl nitrone 1 with POSS containing olefin moieties. The results of cycloaddition processes were rationalized by computational studies at the DFT level. The covalent conjugation of chitosan with the cycloadduct 3a leads to composite material CS-POSS 7 which was gelified using genipin as cross linking agent. The suitability of the system for bone tissue engineering purposes was evaluated by in vitro drug release studies using ketoprofen as a model drug and cytotoxicity assays performed on human fetal osteoblastic cells. The preliminary biological tests showed the lack of cytotoxicity of the hybrid material and suggest its potential role in bone tissue engineering applications.

Supramolecular recognition of phosphocholine by an enzyme-like cavitand receptor.

The first example of supramolecular recognition of phosphocholine by a cavitand receptor has been reported here. The chemical structure of the receptor has been optimized by DFT calculations. The recognition mechanism is based on a "multi-topic approach", which leads to highly efficient (K value up to 107 M-1), selective and sensitive (ppb level) sensing of phosphocholine. The recognition mechanism proposed here is similar to those exploited by Nature, and paves the way for the realization of new sensors with important applications in medicine and security fields.

Novel 3,3-disubstituted oxindole derivatives. Synthesis and evaluation of the anti-proliferative activity.

3,3-Disubstituted oxindole derivatives bearing a nitrogen atom at the C-3 position have been synthesized starting from 3-alkyl oxindole through a metal free pathway. These derivatives have been tested in five human tumor cell lines (PC3, MCF7, SW620, MiaPaca2 and A375) and on primary cells (PBMCs) from healthy donors providing compound 6d showing a strong anticancer effect in all cancer lines on the low micromolar range.

Polystyrene Nanocomposites Reinforced with Novel Dumbbell-Shaped Phenyl-POSSs: Synthesis and Thermal Characterization.

Two series of novel dumbbell-shaped polyhedral oligomeric silsesquioxanes (POSSs), fully functionalized with phenyl groups at the corner of the silicon cages, were used to prepare polystyrene (PS) nanocomposites through the method of in situ polymerization. The percentage of the molecular filler reinforcement was set as 5% w/w of POSS and was checked by 1H-NMR spectroscopy. The obtained nanocomposites were characterized by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). Thermal and morphological properties were evaluated and compared among the nanocomposites obtained using the two different series of dumbbell-shaped POSSs and with the net PS. The thermal parameters for the prepared nanocomposites were very high when compared with those of neat PS, and they evidenced significant differences when an aliphatic or aromatic bridge was used to link the silicon cages. SEM analysis results allow us to hypothesize a justification for the different resistance to thermal degradation showed by the two series of molecular reinforcement.

Transient and intermediate carbocations in ruthenium tetroxide oxidation of saturated rings.

The ruthenium tetroxide-mediated oxidation of cyclopentane, tetrahydrofuran, tetrahydrothiophene and N-substituted pyrrolidines has been studied computationally by DFT and topological (analysis of the electron localization function, ELF) methods. In agreement with experimental observations and previous DFT calculations, the rate-limiting step of the reaction takes place through a highly asynchronous (3 + 2) concerted cycloaddition through a single transition structure (one kinetic step). The ELF analysis identifies the reaction as a typical one-step-two-stages process and corroborates the existence of a transient carbocation. In the case of pyrrolidines, the carbocation is completely stabilized as an energy minimum in the form of an iminium ion and the reaction takes place in two steps.