Novel betulin derivatives inhibit IFN-γ and modulates COX-2 expression

Abstract

Betulin (BE) is a pentacyclic triterpenes, obtained from natural sources and with several biological activities described, such as anti-tumoral and anti-inflammatory activities. The BE esterification at hydroxyl group (C-3 and C-28) resulted in five new ester derivatives with different numbers of carbons or halogens (chlorine and fluorine). Among these BE derivatives, two (2a e 2c) were able to significantly decrease IFN-g (*p?=?0.0391; **p?=?0.0156) and 2c modulated the expression of COX-2 better than Dexamethasone (DEXA). Regarding to cytotoxic assay, the best results were obtained for BE without modifications, with emphasis on tumoral cell lines Raji and MCF-7. The derivatives 2a and 2c showed immunomodulation activity (for the cytokines IFN-g). The presence of chorine in BE seems to be important for the ability of modulate COX-2 expression, since the ester chloride derivative 2c at 100?μM is more powerful inhibitor of COX-2 than DEXA.     

The employment of relativistic adapted Gaussian basis sets in Douglas–Kroll–Hess scalar calculations with diatomic molecules

The prolapse-free relativistic adapted Gaussian basis sets (RAGBSs), developed by our research group on the basis of the four-component approach, are used for the first time in Douglas–Kroll–Hess 2nd order scalar relativistic calculations (DKH2) of simple diatomic molecules containing Hydrogen and the halogens from Fluorine up to Iodine: HX and X₂, where X = F, Cl, Br, and I. To this end, the RAGBSs were contracted with the general contraction scheme to triple-, quadruple-, and quintuple-zeta sets. Polarization functions were also added to the basis sets by optimization with the configuration interaction method including single and double excitations into the DKH2 environment, DKH2-CISD. The molecular properties were then calculated with the coupled cluster electronic correlation treatment and the DKH2 scalar relativistic method, DKH2-CCSD(T), and indicated that our RAGBSs should be contracted as quadruple-zeta basis sets. The results achieved with the DKH2-CCSD(T) calculations and the selected quadruple-zeta RAGBSs are able to reproduce the experimental data of equilibrium distances, dissociation energies, and harmonic vibrational frequencies with root-mean-square (rms) errors of 0.015 Å, 3.6 kcal mol⁻¹, and 21.7 cm⁻¹, respectively.     

Affine Properties of Convex Equal-Area Polygons

In this paper we discuss some affine properties of convex equal-area polygons, which are convex polygons such that all triangles formed by three consecutive vertices have the same area. Besides being able to approximate closed convex smooth curves almost uniformly with respect to affine length, convex equal-area polygons admit natural definitions of the usual affine differential geometry concepts, like affine normal and affine curvature. These definitions lead to discrete analogous to the six-vertex theorem and an affine isoperimetric inequality. One can also define discrete counterparts of the affine evolute, parallels and the affine distance symmetry set preserving many of the properties valid for smooth curves.     

Development,Characterization, and Immunomodulatory Evaluation of Carvacrol-loaded Nanoemulsion

Carvacrol (CV) is an essential oil with numerous therapeutic properties, including immunomodulatory activity. However, this effect has not been studied in nanoemulsion systems. The objective of this study was to develop an innovative carvacrol-loaded nanoemulsion (CVNE) for immunomodulatory action. The developed CVNE comprised of 5% w/w oily phase (medium chain triglycerides + CV), 2% w/w surfactants (Tween 80^®/Span 80^®), and 93% w/w water, and was produced by ultrasonication. Dynamic light scattering over 90 days was used to characterize CVNE. Cytotoxic activity and quantification of cytokines were evaluated in peripheral blood mononuclear cell (PBMC) culture supernatants. CVNE achieved a drug loading of 4.29 mg/mL, droplet size of 165.70 ± 0.46 nm, polydispersity index of 0.14 ± 0.03, zeta potential of −10.25 ± 0.52 mV, and good stability for 90 days. CVNE showed no cytotoxicity at concentrations up to 200 µM in PBMCs. CV diminished the production of IL-2 in the PBMC supernatant. However, CVNE reduced the levels of the pro-inflammatory cytokines IL-2, IL-17, and IFN-γ at 50 µM. In conclusion, a stable CVNE was produced, which improved the CV immunomodulatory activity in PBMCs.     

Polygons with Parallel Opposite Sides

In this paper we consider convex planar polygons with parallel opposite sides. These polygons can be regarded as discretizations of closed convex planar curves by taking tangent lines at samples with pairwise parallel tangents. For such polygons, we define discrete versions of the area evolute, central symmetry set, equidistants, and area parallels and show that they behave quite similarly to their smooth counterparts.     

The Use of Reverse Vaccinology and Molecular Modeling Associated with Cell Proliferation Stimulation Approach to Select Promiscuous Epitopes from <Emphasis Type="Italic">Schistosoma mansoni</Emphasis>

Schistosomiasis remains an important parasitic disease that affects millions of individuals worldwide. Despite the availability of chemotherapy, the occurrence of constant reinfection demonstrates the need for additional forms of intervention and the development of a vaccine represents a relevant strategy to control this disease. With the advent of genomics and bioinformatics, new strategies to search for vaccine targets have been proposed, as the reverse vaccinology. In this work, computational analyses of Schistosoma mansoni membrane proteins were performed to predict epitopes with high affinity for different human leukocyte antigen (HLA)-DRB1. Ten epitopes were selected and along with murine major histocompatibility complex (MHC) class II molecule had their three-dimensional structures optimized. Epitope interactions were evaluated against murine MHC class II molecule through molecular docking, electrostatic potential, and molecular volume. The epitope Sm141290 and Sm050890 stood out in most of the molecular modeling analyses. Cellular proliferation assay was performed to evaluate the ability of these epitopes to bind to murine MHC II molecules and stimulate CD4+ T cells showing that the same epitopes were able to significantly stimulate cell proliferation. This work showed an important strategy of peptide selection for epitope-based vaccine design, achieved by in silico analyses that can precede in vivo and in vitro experiments, avoiding excessive experimentation.     

Metal binding selectivity of oxa-aza macrocyclic ligand: a DFT study of first- and second-row transition metal for four coordination systems

A detailed theoretical study of the 1,7,1l,17-tetraoxa-2,6,12,16-tetraaza-cycloeicosane ligand ([20]AneN₄O₄) coordinated to Fe²⁺, Co²⁺, Ni²⁺, Ru²⁺, Rh²⁺, and Pd²⁺ transition metal ions was carried out with the B3LYP method. Two different cases were performed: when nitrogen is the donor atom (1a _q ) and also with the oxygen as the donor atom (1b _q ). For all the cases performed in this study 1a _q structures were always more stable than the 1b _q ones. Considering each row is possible to see that the energy increases with the increase of the atomic number. The M²⁺ cation binding energies for the 1a _q complexes increase with the following order: Fe²⁺ < Ru²⁺ < Co²⁺ < Ni²⁺ < Rh²⁺ < Pd²⁺.

     

A geometric representation of improper indefinite affine spheres with singularities

Given a pair of planar curves, one can define its generalized area distance, a concept that generalizes the area distance of a single curve. In this paper, we show that the generalized area distance of a pair of planar curves is an improper indefinite affine spheres with singularities, and, reciprocally, every indefinite improper affine sphere in ${\mathbb {R}^3}$ is the generalized distance of a pair of planar curves. Considering this representation, the singularity set of the improper affine sphere corresponds to the area evolute of the pair of curves, and this fact allows us to describe a clear geometric picture of the former. Other symmetry sets of the pair of curves, like the affine area symmetry set and the affine envelope symmetry set can be also used to describe geometric properties of the improper affine sphere.