Artificial Neural Networks for Predicting the Diameter of Electrospun Nanofibers Synthesized from Solutions/Emulsions of Biopolymers and Oils.

In the present work, different configurations of nt iartificial neural networks (ANNs) were analyzed in order to predict the experimental diameter of nanofibers produced by means of the electrospinning process and employing polyvinyl alcohol (PVA), PVA/chitosan (CS) and PVA/aloe vera (Av) solutions. In addition, gelatin type A (GT)/alpha-tocopherol (α-TOC), PVA/olive oil (OO), PVA/orange essential oil (OEO), and PVA/anise oil (AO) emulsions were used. The experimental diameters of the nanofibers electrospun from the different tested systems were obtained using scanning electron microscopy (SEM) and ranged from 93.52 nm to 352.1 nm. Of the three studied ANNs, the one that displayed the best prediction results was the one with three hidden layers with the flow rate, voltage, viscosity, and conductivity variables. The calculation error between the experimental and calculated diameters was 3.79%. Additionally, the correlation coefficient (R2) was identified as a function of the ANN configuration, obtaining values of 0.96, 0.98, and 0.98 for one, two, and three hidden layer(s), respectively. It was found that an ANN configuration having more than three hidden layers did not improve the prediction of the experimental diameter of synthesized nanofibers.

Inhibitory Mechanism of the Isoflavone Derivative Genistein in the Human CaV3.3 Channel.

Regulation of cellular excitability and oscillatory behavior of resting membrane potential in nerve cells are largely mediated by the low-voltage activated T-type calcium channels. This calcium channel family is constituted by three isoforms, namely, CaV3.1, CaV3.2, and CaV3.3, that are largely distributed in the nervous system and other parts of the body. Dysfunction of T-type calcium channels is associated with a wide range of pathophysiologies including epilepsy, neuropathic pain, cardiac problems, and major depressive disorders. Due to their pharmacological relevance, finding molecular agents able to modulate the channel's function may provide therapeutic means to ameliorate their related disorders. Here we used electrophysiological experiments to show that genistein, a canonical tyrosine kinase inhibitor, reduces the activity of the human CaV3.3 channel in a concentration-dependent manner. The inhibitory effect of genistein is independent of tyrosine kinase modulation and does not affect the voltage-dependent gating of the channel. Subsequently, we used computational methods to identify plausible molecular poses for the interaction of genistein and the CaV3.3 channel. Starting from different molecular poses, we carried out all-atom molecular dynamics (MD) simulations to identify the interacting determinants for the CaV3.3/genistein complex formation. Our extensive (microsecond-length) simulations suggest specific binding interactions that seem to stabilize the protein/inhibitor complex. Furthermore, our results from the unbiased MD simulations are in good agreement with the recently solved cryoelectron microscopy structure of the CaV3.1/Z944 complex in terms of both the location of the ligand binding site and the role of several equivalent amino acid residues. Proposed interacting complex loci were subsequently tested and corroborated by electrophysiological experiments using another naturally occurring isoflavone derivative, daidzein. Thus, by using a combination of in vitro and in silico techniques, we have identified interacting determinants relevant to the CaV3.3/genistein complex formation and propose that genistein directly blocks the function of the human CaV3.3 channel as a result of such interaction. Specifically, we proposed that a combination of polar interactions involving the three hydroxyl groups of genistein and an aromatic interaction with the fused rings are the main binding interactions in the complex formation. Our results pave the way for the rational development of improved and novel low-voltage activated T-type calcium channel inhibitors.

Decavanadate Salts of Cytosine and Metformin: A Combined Experimental-Theoretical Study of Potential Metallodrugs Against Diabetes and Cancer.

Cytosine, a DNA and RNA building-block, and Metformin, the most widely prescribed drug for the treatment of Type 2 Diabetes mellitus were made to react separately with ammonium or sodium metavanadates in acidic aqueous solutions to obtain two polyoxovanadate salts with a 6:1 ratio of cation-anion. Thus, compounds [HCyt]6[V10O28]·4H2O, 1 and [HMetf]6[V10O28]·6H2O, 2 (where HCyt = Cytosinium cation, [C4H6N3O]+ and HMetf = Metforminium cation, [C4H12N5]+) were obtained and characterized by elemental analysis, single crystal X-ray diffraction, vibrational spectroscopy (IR and Raman), solution 51V-NMR, thermogravimetric analysis (TGA-DTGA), as well as, theoretical methods. Both compounds crystallized in P 1 ¯   space group with Z' = 1/2, where the anionic charge of the centrosymmetric ion [V10O28]6- is balanced by six Cytosinium and six Metforminium counterions, respectively. Compound 1 is stabilized by π-π stacking interactions coming from the aromatic rings of HCyt cations, as denoted by close contacts of 3.63 Å. On the other hand, guanidinium moieties from the non-planar HMetf in Compound 2 interact with decavanadate µ2-O atoms via N-H···O hydrogen bonds. The vibrational spectroscopic data of both IR and Raman spectra show that the dominant bands in the 1000-450 cm-1 range are due to the symmetric and asymmetric ν(V-O) vibrational modes. In solution, 51V-NMR experiments of both compounds show that polyoxovanadate species are progressively transformed into the monomeric, dimeric and tetrameric oxovanadates. The thermal stability behavior suggests a similar molecular mechanism regarding the loss of water molecules and the decomposition of the organic counterions. Yet, no changes were observed in the TGA range of 540-580°C due to the stability of the [V10O28]6- fragment. Dispersion-corrected density functional theory (DFT-D) calculations were carried out to model the compounds in aqueous phase using a polarized continuum model calculation. Optimized structures were obtained and the main non-covalent interactions were characterized. Biological activities of these compounds are also under investigation. The combination of two therapeutic agents opens up a window toward the generation of potential metalopharmaceuticals with new and exciting pharmacological properties.