Liposomal Epigallocatechin-3-Gallate for the Treatment of Intestinal Dysbiosis in Children with Autism Spectrum Disorder: A Comprehensive Review.

Autism Spectrum Disorder (ASD) is characterized by varying degrees of difficulty in social interaction and communication. These deficits are often associated with gastrointestinal symptoms, indicating alterations in both intestinal microbiota composition and metabolic activities. The intestinal microbiota influences the function and development of the nervous system. In individuals with ASD, there is an increase in bacterial genera such as Clostridium, as well as species involved in the synthesis of branched-chain amino acids (BCAA) like Prevotella copri. Conversely, decreased amounts of Akkermansia muciniphila and Bifidobacterium spp. are observed. Epigallocatechin-3-gallate (EGCG) is one of the polyphenols with the greatest beneficial activity on microbial growth, and its consumption is associated with reduced psychological distress. Therefore, the objective of this review is to analyze how EGCG and its metabolites can improve the microbial dysbiosis present in ASD and its impact on the pathology. The analysis reveals that EGCG inhibits the growth of pathogenic bacteria like Clostridium perfringens and Clostridium difficile. Moreover, it increases the abundance of Bifidobacterium spp. and Akkermansia spp. As a result, EGCG demonstrates efficacy in increasing the production of metabolites involved in maintaining epithelial integrity and improving brain function. This identifies EGCG as highly promising for complementary treatment in ASD.

Classification of Congeneric and QSAR of Homologous Antileukemic S-Alkylcysteine Ketones.

Based on a set of six vector properties, the partial correlation diagram is calculated for a set of 28 S-alkylcysteine diazomethyl- and chloromethyl-ketone derivatives. Those with the greatest antileukemic activity in the same class correspond to high partial correlations. A periodic classification is performed based on information entropy. The first four characteristics denote the group, and the last two indicate the period. Compounds in the same period and, especially, group present similar properties. The most active substances are situated at the bottom right. Nine classes are distinguished. The principal component analysis of the homologous compounds shows five subclasses included in the periodic classification. Linear fits of both antileukemic activities and stability are good. They are in agreement with the principal component analysis. The variables that appear in the models are those that show positive loading in the principal component analysis. The most important properties to explain the antileukemic activities (50% inhibitory concentration Molt-3 T-lineage acute lymphoblastic leukemia minus the logarithm of 50% inhibitory concentration Nalm-6 B-lineage acute lymphoblastic leukemia and stability k) are ACD logD, surface tension and number of violations of Lipinski's rule of five. After leave-m-out cross-validation, the most predictive model for cysteine diazomethyl- and chloromethyl-ketone derivatives is provided.

Structure-Activity Relationships of Cytotoxic Lactones as Inhibitors and Mechanisms of Action.

BACKGROUND: Some lactones prevent protein Myb-dependent gene expression. OBJECTIVE: The object is to calculate inhibitors of Myb-brought genetic manifestation. METHODS: Linear quantitative structure-potency relations result expanded, among sesquiterpene lactones of a variety of macrocycles (pseudoguaianolides, guaianolides, eudesmanolides and germacranolides), to establish which part of the molecule constitutes their pharmacophore, and predict their inhibitory potency on Myb-reliant genetic manifestation, which may result helpful as leads for antileukaemic therapies with a new mechanism of action. RESULTS: Several count indices are connected with structure-activity. The α-methylene-γ-lactone ML functional groups increase, whereas OH groups decrease the activity. Hydrophobicity provides to increase cell toxicity. Four counts (ML, number of α, ß-unsaturated CO groups, etc.), connected with the number of oxygens, present a positive association, owing to the partial negative charge of oxygen. The s-trans-strans- germacranolide molecule presents maximal potency. The OH groups decrease the potency owing to the positive charge of hydrogen. The numbers of π-systems and atoms, and polarizability increase the potency. Following least squares, every standard error of the coefficients is satisfactory in every expression. The most predictive linear expressions for lactones, pseudoguaianolides and germacranolides are corroborated by leave-group-out cross-validation. Quadratic equations do not make the correlation better. CONCLUSION: Likely action mechanisms for lactones are argued with a diversity of functional groups in the lactone annulus, including artemisinin with its uncommon macrocycle characteristic, 1,2,4-trioxane cycle (pharmacophoric peroxide linkage -O1-O2- in endoperoxide ring), which results in the foundation for its sole antimalarial potency.

QSAR of Natural Sesquiterpene Lactones as Inhibitors of Myb-dependent Gene Expression.

BACKGROUND: Protein c-Myb is a therapeutic target. Some sesquiterpene lactones suppress Myb-dependent gene expression, which results in their potential anti-cancer activity. MATERIAL & METHODS: Database ChEMBL is a representative of lactones for physicochemical and physiochemical properties. Data presented for 31 natural lactones are discussed in terms of quantitative structureactivity relationships with the objective to predict inhibitors of Myb-induced gene expression. Several constitutional descriptors are related to structure-activity. α-Methylene-γ-lactone groups enhance while OH functions worsen potency. The latter feature is in agreement with the fact that the more lipophilic the lactone, the greater the cytotoxicity because of the ability to cross lipoidal biomembranes. In general, numbers of π-systems and atoms, and polarizability enhance activity. Linear and nonlinear structure-activity models are developed, between lactones of a great structural diversity, to predict inhibitors of Myb-induced gene expression. Four variables (ML, UNC, TCO+OCOR, UNC+UNA) related to ATOM show a positive correlation because of the partial anionic and H-acceptor characters of O-atom. In most, CO group is conjugated. RESULT AND CONCLUSION: Term OH shows negative coefficients because of the partial cationic quality of H-atom and because OH forms H-bonds with CO, causing them to be less H-acceptor. s-trans-s-trans-Germacranolide structure is the most active. Coefficients standard errors result acceptable in almost all equations. After cross-validation, linear equations for lactones, pseudoguaianolides and germacranolides are the most predictive. Most descriptors are constitutional variables.

Larvicidal activity prediction against Aedes aegypti mosquito using computational tools.

BACKGROUND & OBJECTIVES: Aedes aegypti is an important vector for transmission of dengue, yellow fever, chikun- gunya, arthritis, and Zika fever. According to the World Health Organization, it is estimated that Ae. aegypti causes 50 million infections and 25,000 deaths per year. Use of larvicidal agents is one of the recommendations of health organizations to control mosquito populations and limit their distribution. The aim of present study was to deduce a mathematical model to predict the larvicidal action of chemical compounds, based on their structure. METHODS: A series of different compounds with experimental evidence of larvicidal activity were selected to develop a predictive model, using multiple linear regression and a genetic algorithm for the selection of variables, implemented in the QSARINS software. The model was assessed and validated using the OECDs principles. RESULTS: The best model showed good value for the determination coefficient (R2 = 0.752), and others parameters were appropriate for fitting (s = 0.278 and RMSEtr = 0.261). The validation results confirmed that the model hasgood robustness (Q2LOO = 0.682) and stability (R2-Q2LOO = 0.070) with low correlation between the descriptors (KXX = 0.241), an excellent predictive power (R2 ext = 0.834) and was product of a non-random correlation R2 Y-scr = 0.100). INTERPRETATION & CONCLUSION: The present model shows better parameters than the models reported earlier in the literature, using the same dataset, indicating that the proposed computational tools are more efficient in identifying novel larvicidal compounds against Ae. aegypti.

Polyphenolic Phytochemicals in Cancer Prevention and Therapy: Bioavailability versus Bioefficacy.

Natural polyphenols are organic chemicals which contain phenol units in their structures. They show antitumor properties. However, a key problem is their short half-life and low bioavailability under in vivo conditions. Still, definitively demonstrating the human benefits of isolated polyphenolic compounds (alone or in combination) using modern scientific methodology has proved challenging. The most common discrepancy between experimental and clinical observations is the use of nonphysiologically relevant concentrations of polyphenols in mechanistic studies. Thus, it remains highly controversial how applicable underlying mechanisms are with bioavailable concentrations and biological half-life. The present Perspective analyses proposed antitumor mechanisms, in vivo reported antitumor effects, and possible mechanisms that may explain discrepancies between bioavailability and bioefficacy. Polyphenol metabolism and possible toxic side effects are also considered. Our main conclusion emphasizes that these natural molecules (and their chemical derivatives) indeed can be very useful, not only as cancer chemopreventive agents but also in oncotherapy.

Quantitative Structure-Antioxidant Activity Models of Isoflavonoids: A Theoretical Study.

Seventeen isoflavonoids from isoflavone, isoflavanone and isoflavan classes are selected from Dalbergia parviflora. The ChEMBL database is representative from these molecules, most of which result highly drug-like. Binary rules appear risky for the selection of compounds with high antioxidant capacity in complementary xanthine/xanthine oxidase, ORAC, and DPPH model assays. Isoflavonoid structure-activity analysis shows the most important properties (log P, log D, pKa, QED, PSA, NH + OH ≈ HBD, N + O ≈ HBA). Some descriptors (PSA, HBD) are detected as more important than others (size measure Mw, HBA). Linear and nonlinear models of antioxidant potency are obtained. Weak nonlinear relationships appear between log P, etc. and antioxidant activity. The different capacity trends for the three complementary assays are explained. Isoflavonoids potency depends on the chemical form that determines their solubility. Results from isoflavonoids analysis will be useful for activity prediction of new sets of flavones and to design drugs with antioxidant capacity, which will prove beneficial for health with implications for antiageing therapy.

Computational Study of Nanosized Drug Delivery from Cyclodextrins, Crown Ethers and Hyaluronan in Pharmaceutical Formulations.

The problem in this work is the computational characterization of cyclodextrins, crown ethers and hyaluronan (HA) as hosts of inclusion complexes for nanosized drug delivery vehicles in pharmaceutical formulations. The difficulty is addressed through a computational study of some thermodynamic, geometric and topological properties of the hosts. The calculated properties of oligosaccharides of D-glucopyranoses allow these to act as co-solvents of polyanions in water. In crown ethers, the central channel is computed. Mucoadhesive polymer HA in formulations releases drugs in mucosas. Geometric, topological and fractal analyses are carried out with code TOPO. Reference calculations are performed with code GEPOL. From HA to HA·3Ca and hydrate, the hydrophilic solvent-accessible surface varies with the count of H-bonds. The fractal dimension rises. The dimension of external atoms rises resulting 1.725 for HA. It rises going to HA·3Ca and hydrate. Nonburied minus molecular dimension rises and decays. Hydrate globularity is lower than O(water), Ca(2+) and O(HA). Ca(2+) rugosity is smaller than for hydrate, O(HA) and O(water). Ca(2+) and O(water) accessibilities are greater than hydrate. Conclusions are drawn on: (1) the relative stability of linear/cyclic and shorter/larger polymers; (2) the atomic analysis of properties allows determining the atoms with maximum reactivity.

Information entropy-based classification of triterpenoids and steroids from Ganoderma.

A set of 71 triterpenoid and steroid compounds from Ganoderma were periodically classified using a procedure based on information entropy with artificial intelligence. Six features were used in hierarchical order to classify the triterpenoids and steroids structurally. The phytochemicals belonging to the same group in the periodic table present similar antioxidant activity, and those compounds belonging to the same period exhibit maximum resemblance. The periodic classification is related to the experimental bioactivity and antioxidant potency data that are available in the literature: a steroid with a three-ketone group conjugated with two carbon-carbon double bonds in the right side of the periodic table exhibits the greatest antioxidant activity.

Molecular classification of pesticides including persistent organic pollutants, phenylurea and sulphonylurea herbicides.

Pesticide residues in wine were analyzed by liquid chromatography-tandem mass spectrometry. Retentions are modelled by structure-property relationships. Bioplastic evolution is an evolutionary perspective conjugating effect of acquired characters and evolutionary indeterminacy-morphological determination-natural selection principles; its application to design co-ordination index barely improves correlations. Fractal dimensions and partition coefficient differentiate pesticides. Classification algorithms are based on information entropy and its production. Pesticides allow a structural classification by nonplanarity, and number of O, S, N and Cl atoms and cycles; different behaviours depend on number of cycles. The novelty of the approach is that the structural parameters are related to retentions. Classification algorithms are based on information entropy. When applying procedures to moderate-sized sets, excessive results appear compatible with data suffering a combinatorial explosion. However, equipartition conjecture selects criterion resulting from classification between hierarchical trees. Information entropy permits classifying compounds agreeing with principal component analyses. Periodic classification shows that pesticides in the same group present similar properties; those also in equal period, maximum resemblance. The advantage of the classification is to predict the retentions for molecules not included in the categorization. Classification extends to phenyl/sulphonylureas and the application will be to predict their retentions.

Cluster solvation models of carbon nanostructures: extension to fullerenes, tubes, and buds.

Carbon nanobud (CNB), a hybrid material consisting of single-wall C-nanotubes (CNTs) (SWNTs) with covalently attached fullerenes, in cluster form is discussed in organic solvents. Theories are developed based on bundlet and droplet models describing size-distribution functions. Phenomena present a unified explanation in bundlet model in which free energy of CNBs involved in cluster is combined from two parts: a volume one proportional to the number of molecules n in aggregate and a surface one, to n(1/2). Bundlet model enables describing distribution function of CNB clusters by size. From purely geometrical considerations bundlet (SWNT/CNB) and droplet (fullerene) models predict dissimilar behaviors. Interaction-energy parameters of CNBs are taken from C60. A C60/SWNT in-between behavior is expected; however, properties of CNBs result closer to SWNTs. Smaller CNB clusters result less stable but greater ones are more stable than SWNT bundles. The solubility decays with temperature result smaller for SWNT/CNB than C60 in agreement with lower number of units in aggregates. Discrepancy between the experimental data of heat of solution of fullerenes and CNT/CNBs is ascribed to sharp concentration dependence of heat of solution. Diffusion coefficient decays with temperature and results greater for CNB than SWNT or C60. Clusters (C60)13 and SWNT/CNB7 are representative of droplet and bundlet models.

QSPR prediction of chromatographic retention times of pesticides: partition and fractal indices.

The high-performance liquid-chromatographic retentions of red-wine pesticide residues are modeled by structure-property relationships. The effect of different types of features is analyzed: geometric, lipophilic, etc. The properties are fractal dimensions, partition coefficient, etc., in linear and nonlinear correlation models. Biological plastic evolution is an evolutionary perspective conjugating the effect of acquired characters and relations that emerge among the principles of evolutionary indeterminacy, morphological determination and natural selection. It is applied to design the co-ordination index that is used to characterize pesticide retentions. The parameters used to calculate the co-ordination index are the molar formation enthalpy, molecular weight and surface area. The morphological and co-ordination indices barely improve the correlations. The fractal dimension averaged for non­buried atoms, partition coefficient, etc. distinguishes the pesticide molecular structures. The structural and constituent classification is based on nonplanarity, and the number of cycles, and O, S, N and Cl atoms. Different behavior depends on the number of cycles.

Classification of stilbenoid compounds by entropy of artificial intelligence.

A set of 66 stilbenoid compounds is classified into a system of periodic properties by using a procedure based on artificial intelligence, information entropy theory. Eight characteristics in hierarchical order are used to classify structurally the stilbenoids. The former five features mark the group or column while the latter three are used to indicate the row or period in the table of periodic classification. Those stilbenoids in the same group are suggested to present similar properties. Furthermore, compounds also in the same period will show maximum resemblance. In this report, the stilbenoids in the table are related to experimental data of bioactivity and antioxidant properties available in the technical literature. It should be noted that stilbenoids with glycoxyl groups esterified with benzoic acid derivatives, in the group g11000 in the extreme right of the periodic table, show the greatest antioxidant activity as confirmed by experiments in the bibliography. Moreover, the second group from the right (g10111) contains E-piceatannol, which antioxidant activity is recognized in the literature. The experiments confirm our results of the periodic classification.

Classification of flavonoid compounds by using entropy of information theory.

A total of 74 flavonoid compounds are classified into a periodic table by using an algorithm based on the entropy of information theory. Seven features in hierarchical order are used to classify structurally the flavonoids. From these features, the first three mark the group or column, while the last four are used to indicate the row or period in a table of periodic classification. Those flavonoids in the same group and period are suggested to show maximum similarity in properties. Furthermore, those with only the same group will present moderate similarity. In this report, the flavonoid compounds in the table, whose experimental data in bioactivity and antioxidant properties have been previously published, are related.

Information theoretic entropy for molecular classification: oxadiazolamines as potential therapeutic agents.

In this review we present algorithms for classification and taxonomy based on information entropy, followed by structure-activity relationship (SAR) models for the inhibition of human prostate carcinoma cell line DU-145 by 26 derivatives of N-aryl-N-(3-aryl-1,2,4-oxadiazol-5-yl)amines (NNAs). The NNAs are classified using two characteristic chemical properties based on different regions of the molecules. A table of periodic properties of inhibitors of DU-145 human prostate carcinoma cell line is obtained based on structural features from the amine moiety and from the oxadiazole ring. Inhibitors in the same group and period of the periodic table are predicted to have highly similar properties, and those located only in the same group will present moderate similarity. The results of a virtual screening campaign are presented.

QSPR prediction of retention times of phenylurea herbicides by biological plastic evolution.

A simple/sensitive high-performance liquid chromatographic method, with ultraviolet (UV) detection, was developed for phenylurea-herbicide analysis, which involves preconcentration using solid-phase extraction. Mobile phase was acetonitrile/water at flow-rate of 1 mL.min-1 with direct UV absorbance detection at 210 nm. Analyte separation studied on a C18 column was applied successfully to herbicide analysis in soft drink's brands and tap water. Good linearity/repeatability was observed for all pesticides. Retention times increase as: metoxuron < monuron < diuron < matazachlor < linuron. They are modelled by structure-property relations. The effect of different types of features is analyzed: electronic, solvation, lipophilic and steric, etc. Formation enthalpy and molecular dipole moment are calculated with MOPAC-AM1. Most important properties are hydration free energy and dipole moment. Results are improved if competitive conformation with higher dipole moment is considered at 1.1kJ.mol-1. Plastic evolution is an evolutionary perspective conjugating the effect of acquired characters, and relations that emerge among the principles of evolutionary indeterminacy, morphologic determination and natural selection. Plastic evolution is applied to design co-ordination index Ic, which is used to characterize phenylurea herbicides and compared to molecular dipole moment for retention time. Parametres needed to calculate Ic are formation enthalpy and molecular weight/surface area. Ic improves multivariable regression equations for retention and is predictive when it is used together with dipole and hydration free energy. Correction introduced in retention is produced in the correct direction. Hierarchical quantitative structure-property relationship provided simplified properties analysis. Structural classification is based on the presence of two Cl/O/N atoms.

Cooperativity of protein binding to vesicles.

Electrostatics role is studied in protein adsorption to phosphatidylcholine (PC) and PC/phosphatidylglycerol (PG) small unilamellar vesicles (SUVs). Protein interaction is monitored vs. PG content at low ionic strength. Adsorption of lysozyme, myoglobin and bovine serum albumin (BSA) isoelectric point (pI) is investigated in SUVs, along with changes in protein fluorescence emission spectra. Partition coefficients and cooperativity parameters are calculated. At pI, binding is maximum while at lower/higher pHs binding drops. In Gouy-Chapman model activity coefficient goes with square charge number, which deviations indicate asymmetric location of anionic lipid in the bilayer inner leaflet, in agreement with experiments and molecular dynamics simulations. Vesicles bind myoglobin anti-cooperatively and lysozyme/BSA cooperatively. Hill coefficient reflects subunit cooperativity of bi/tridomain proteins.

(Co-)solvent selection for single-wall carbon nanotubes: best solvents, acids, superacids and guest-host inclusion complexes.

Analysis of 1-octanol-water, cyclohexane-water and chloroform (CHCl(3))-water partition coefficients P(o-ch-cf) allows calculation of molecular lipophilicity patterns, which show that for a given atom log P(o-ch-cf) is sensitive to the presence of functional groups. Program CDHI does not properly differentiate between non-equivalent atoms. The most abundant single-wall carbon nanotube (SWNT), (10,10), presents a relatively small aqueous solubility and large elementary polarizability, P(o-ch-cf) and kinetic stability. The SWNT solubility is studied in various solvents, finding a class of non-hydrogen-bonding Lewis bases with good solubility. Solvents group into three classes. The SWNTs in some organic solvents are cationic while in water/Triton X mixture are anionic. Categorized solubility is semiquantitatively correlated with solvent parameters. The coefficient of term ß is positive while the ones of ε and V negative. The electron affinity of d-glucopyranoses (d-Glcp(n)) suggests the formation of colloids of anionic SWNTs in water. Dipole moment for d-Glcp(n)-linear increases with n until four in agreement with 18-fold helix. The I(n)(z-) and SWNT(-) are proposed to form inclusion complexes with cyclodextrin (CD) and amylose (Amy). Starch, d-Glcp, CD and Amy are proposed as SWNT co-solvents. Guests-hosts are unperturbed. A central channel expansion is suggested.

Fullerite crystal thermodynamic characteristics and the law of corresponding states.

The existence of single-wall carbon nanotubes in organic solvents in the form of clusters is discussed. A theory is developed based on a bundlet model, which enables describing the cluster-size distribution function. Comparison of calculated solubilities with experiments would permit obtaining energetic parameters, characterizing the interaction of a nanotube with its surrounding. Fullerenes and nanotubes are objects whose behaviour in many physical situations is characterized by peculiarities, which show up in that these systems represent the only soluble forms of carbon, what is related to their molecular structures. The fullerene molecule is a virtually uniform closed spherical-spheroidal surface and a nanotube is a smooth cylindrical unit. Both structures give rise to weak interactions between the neighbouring units in a crystal and promote their interaction with solvent molecules. The phenomena have a unified explanation in the bundlet model, in which the free energy of a nanotube in a cluster is combined from two components: a volume one proportional to the number of molecules n in a cluster and a surface one proportional to n1/2. Growth mechanisms of fractal clusters in fullerene solutions are analyzed along with similarity laws, determining the thermodynamic characteristics of fullerite crystals. In accordance with the similarity laws, the dimensionless Debye temperatures theta0 for all crystals belonging to the considered class should be close. Temperatures theta0 are determined by a similarity relation from experimental and estimated data. Fullerite theta0 is twice that for inert-gas crystals because, near the Debye point, the fullerite crystal is orientationally ordered so that its structure is dissimilar to face-centred cubic. A fullerene molecule whose thermal rotation is frozen cannot be considered as a spherically symmetric particle. The fulfilment of the similarity laws, which are valuable for particles with spherically symmetric interaction potential, would hardly be expected.

Comparative analysis of the electrostatics of the binding of cationic proteins to vesicles: asymmetric location of anionic phospholipids.

The role of electrostatics is studied in the adsorption of cationic proteins to zwitterionic phosphatidylcholine (PC) and anionic PC/phosphatidylglycerol (PG) mixed small unilamellar vesicles (SUVs). For model proteins the interaction is monitored vs. PG content at low ionic strength. The adsorption of lysozyme and myoglobin (isoelectric point, pI 7-11) is investigated in SUVs, along with changes of the fluorescence emission spectra of the cationic proteins, via their adsorption on SUVs. In the Gouy-Chapman formalism, the activity coefficient goes with the square of charge number. Deviations from the ideal model could indicate the asymmetric location of the anionic phospholipid in the bilayer inner leaflet, in mixed zwitterionic/anionic SUVs for both lysozyme- and myoglobin-PC/PG systems, in agreement with experiments and molecular dynamics simulations. Fitted effective SUV charge stays constant. Effective-formal difference increases 0.417 e.u. Effective protein charge increases as PC/PG