miRNome Profiling and Functional Analysis Reveal Involvement of hsa-miR-1246 in Colon Adenoma-Carcinoma Transition by Targeting AXIN2 and CFTR

Regulatory changes occurring early in colorectal cancer development remain poorly investigated. Since the majority of cases develop from polyps in the adenoma-carcinoma transition, a search of early molecular features, such as aberrations in miRNA expression occurring prior to cancer development, would enable identification of potentially causal, rather than consequential, candidates in the progression of polyp to cancer. In the current study, by employing small RNA-seq profiling of colon biopsy samples, we described differentially expressed miRNAs and their isoforms in the adenoma-carcinoma transition. Analysis of healthy-adenoma-carcinoma sequence in an independent validation group enabled us to identify early deregulated miRNAs including hsa-miR-1246 and hsa-miR-215-5p, the expressions of which are, respectively, gradually increasing and decreasing. Loss-of-function experiments revealed that inhibition of hsa-miR-1246 lead to reduced cell viability, colony formation, and migration rate, thereby indicating an oncogenic effect of this miRNA in vitro. Subsequent western blot and luciferase reporter assay provided evidence of hsa-miR-1246 being involved in the regulation of target AXIN2 and CFTR genes’ expression. To conclude, the present study revealed possible involvement of hsa-miR-1246 in early colorectal cancer development and regulation of tumor suppressors AXIN2 and CFTR.     

Novel Design of Neuropeptide-Based Drugs with β-Sheet Breaking Potential in Amyloid-Beta Cascade: Molecular and Structural Deciphers

Our work discusses the investigation of 75 peptide-based drugs with the potential ability to break the β-sheet structures of amyloid-beta peptides from senile plaques. Hence, this study offers a unique insight into the design of neuropeptide-based drugs with β-sheet breaker potential in the amyloid-beta cascade for Alzheimer’s disease (AD). We started with five peptides (¹⁵QKLVFF²⁰, ¹⁶KLVFF²⁰, ¹⁷LVFF²⁰, ¹⁶KLVF¹⁹ and ¹⁵QKLV¹⁸), to which 14 different organic acids were attached at the N-terminal. It was necessary to evaluate the physiochemical features of these sequences due to the biological correlation with our proposal. Hence, the preliminary analysis of different pharmacological features provided the necessary data to select the peptides with the best biocompatibility for administration purposes. Our approaches demonstrated that the peptides ¹⁷LVFF²⁰, NA-¹⁷LVFF²⁰, ¹⁶KLVF¹⁹ and NA-¹⁶KLVF¹⁹ (NA-nicotinic acid) have the ability to interfere with fibril formation and hence improve the neuro and cognitive functions. Moreover, the peptide conjugate NA-¹⁶KLVF¹⁹ possesses attractive pharmacological properties, demonstrated by in silico and in vitro studies. Tandem mass spectrometry showed no fragmentation for the spectra of ¹⁶KLVF¹⁹. Such important results suggest that under the action of protease, the peptide cleavage does not occur at all. Additionally, circular dichroism confirmed docking simulations and showed that NA-¹⁶KLVF¹⁹ may improve the β-sheet breaker mechanism, and thus the entanglement process of amyloid-beta peptides can be more effective.     

Synthesis of hybrid nanocomposites based on new triazeno copolymers and montmorillonite used for detecting metal ions

The modern synthesis of novel functional materials with improved properties includes that of hybrid nanocomposites composed of inorganic nanoparticles and organic derivatives, where controlling the molecular structure at atomic and macroscopic dimensions is a key factor, with a major effect on performance. An extension of this approach to the field of nanocomposites containing photopolymers with triazene groups attached on a methacrylic backbone could be of great interest in the future development of chemosensors and photoresists, among others. Photopolymer/clay nanocomposites were prepared by in situ free radical copolymerization of 1‐(phenyl)‐3‐(2‐methacryloyloxyethylcarbamoyloxyethyl)‐3‐methyltriazene‐1 or 1‐(p‐methoxyphenyl)‐3‐(2‐methacryloyloxyethylcarbamoyloxyethyl)‐3‐methyltriazene‐1 and vinyl acetate or styrene in solution and in the presence of 3 and 5 wt% of organically modified montmorillonite. The characterization of the nanocomposites and pure copolymers was achieved through ¹H NMR and Fourier transform infrared spectroscopy, gel permeation chromatography, thermogravimetric analysis, X‐ray diffraction, atomic force microscopy and fluorescence analysis. The morphologies and properties of the nanocomposites are dependent on the nature of the triazene, on the co‐monomer structure and on the organoclay content. Also, the fluorescence response of these nanocomposites towards certain metal ions (Fe³⁺, Cu²⁺, Hg²⁺, Ni²⁺) in dimethylformamide solution was investigated. The effect of uranyl ions on the fluorescence intensity of the nanocomposites in solution or as films could be exploited in the development of ‘turn‐off’ or ‘turn‐on’ chemosensors for this type of analyte. Triazeno copolymer/organophilic montmorillonite nanocomposites with exfoliated (not completely exfoliated) or exfoliated and intercalated structures exhibit distinct characteristics concerning their fluorescence behaviour, a higher sensing ability towards certain target compounds (Fe³⁺, UO₂²⁺) being evidenced for those incorporating 3 wt% organoclay in solution and as films. Copyright © 2010 Society of Chemical Industry     

Adsorption of Zn(II) by crosslinked acrylic copolymers with amine functional groups

Adsorption of Zn(II) ions from diluted aqueous solutions by the acrylic copolymer based on ethylacrylate : acrylonitrile : divinylbenzene matrix with different crosslinking degrees and ethylenediamine and triethylenetetramine functional groups was investigated. Adsorption experiments were carried out by batch method. The effects of the pH, initial concentration of zinc, time of contact, and the crosslinking degree of the copolymers were studied. On the basis of Langmuir and Freundlich isotherms, the parameters that characterize the adsorption were determined. The maximum Zn(II) retention capacity value (500 mg g^?1) was obtained for the acrylic copolymer with 2% crosslinking degree and ethylenediamine, as functional groups. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 803–808, 2004     

Retention of gallium ions from acidic solutions by pyridine strong‐base anion exchangers

Using the batch method, the retention of Ga(III) from HCl solutions by two gel‐type pyridine strong‐base anion exchangers containing 1‐methyl‐ or 1‐butyl‐4‐vinylpyridinium chloride structural units, called S₁ and S₂ resins, respectively, was studied. The influence of the HCl and Ga(III) concentrations as well as of the contact time between the resin and the liquid phase was investigated. The parameters, which characterize the retention process, were estimated using Langmuir and Freundlich isotherms. Both resins exhibited a higher affinity for gallium ions from a 6M HCl solution. According to Langmuir isotherms, maximum retention capacities of 44.44 and 60 mg Ga(III)/g dry resin for the S₁ and S₂ resins, respectively, were obtained. Freundlich isotherms provide additional proof for a higher affinity of the S₂ resin for Ga(III) from HCl solutions. It is clear that the substituent length increase on N⁺ atoms led to an increasing affinity of the pyridine strong base anion exchangers toward Ga(III). © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 86: 3440–3444, 2002     

Discovery of novel non-cyclam polynitrogenated CXCR4 coreceptor inhibitors

HIV cell fusion and entry have been validated as targets for therapeutic intervention against infection. Bicyclams were the first low-molecular-weight compounds to show specific interaction with CXCR4. The most potent bicyclam was AMD3100, in which the two cyclam moieties are tethered by a 1,4-phenylenebis(methylene) bridge. It was withdrawn from clinical trials owing to its lack of oral bioavailability and cardiotoxicity. We have designed a combinatorial library of non-cyclam polynitrogenated compounds by preserving the main features of AMD3100. At least two nitrogen atoms on each side of the p-phenylene moiety, one in the benzylic position and the other(s) in the heterocyclic system were maintained, and the distances between them were similar to the nitrogen atom distances in cyclam. A selection of diverse compounds from this library were prepared, and their in vitro activity was tested in cell cultures against HIV strains. This led to the identification of novel potent CXCR4 coreceptor inhibitors without cytotoxicity at the tested concentrations.     

Possibilities of using the ultrasonic wave transmission method to estimate initial setting time of cement paste

In this paper, the applicability of the ultrasonic wave transmission method to estimate the initial setting time of an arbitrary cement paste is discussed. Ultrasonic pulse velocity measurements were fully automated and measured continuously. The Vicat Needle Test was used in order to determine the initial setting time of cement pastes. Different cement pastes were prepared in order to check the influence of the water/cement ratio, type of cement, curing temperature, cement fineness, and some clinker compositions, on the relationship between the initial setting time and ultrasonic pulse velocity. It was found that the initial setting time of an arbitrary cement paste can be estimated very accurately by the time the first inflection point appears on the ultrasonic pulse velocity curve. Moreover, it can be estimated quite accurately by the time the ultrasonic pulse velocity reaches a fixed value, close to the value of the ultrasonic pulse velocity in water.     

Synergy in Cystic Fibrosis Therapies: Targeting SLC26A9

SLC26A9, a constitutively active Cl⁻ transporter, has gained interest over the past years as a relevant disease modifier in several respiratory disorders including Cystic Fibrosis (CF), asthma, and non-CF bronchiectasis. SLC26A9 contributes to epithelial Cl⁻ secretion, thus preventing mucus obstruction under inflammatory conditions. Additionally, SLC26A9 was identified as a CF gene modifier, and its polymorphisms were shown to correlate with the response to drugs modulating CFTR, the defective protein in CF. Here, we aimed to investigate the relationship between SLC26A9 and CFTR, and its role in CF pathogenesis. Our data show that SLC26A9 expression contributes to enhanced CFTR expression and function. While knocking-down SLC26A9 in human bronchial cells leads to lower wt- and F508del-CFTR expression, function, and response to CFTR correctors, the opposite occurs upon its overexpression, highlighting SLC26A9 relevance for CF. Accordingly, F508del-CFTR rescue by the most efficient correctors available is further enhanced by increasing SLC26A9 expression. Interestingly, SLC26A9 overexpression does not increase the PM expression of non-F508del CFTR traffic mutants, namely those unresponsive to corrector drugs. Altogether, our data indicate that SLC26A9 stabilizes CFTR at the ER level and that the efficacy of CFTR modulator drugs may be further enhanced by increasing its expression.     

Characteristics of Zinc Corrosion and Formation of Conversion Films on the Zinc Surface in Acidic Solutions of Cr(III) Compounds

The influence of the components of an acidic solution: Cr(III) nitrate-malonic acid-Co(II) salt and treatment conditions on zinc dissolution and formation of Chromate films as well as on their decorative and protective properties have been studied using the analytical, XPS, structural and accelerated corrosion test methods. An organic acid is the main component, which has an essential influence on zinc dissolution and formation of Chromate films as well as their decorative and protective properties. The influence of organic acid is directly related with the state of the Cr³⁺ ions in chromating solution. When the Cr³⁺ ions are in the form of hexaaquaions, the organic acid increases the quantities of the zinc dissolved and the Cr(III) deposited on the zinc surface (especially at 60°C). It also predetermines the formation of a thick, porous Chromate film with large cracks at 60°C. Its decorative and protective properties are rather poor. When Cr³⁺ ions are in the form of a complex with organic acid, the quantities of the zinc dissolved and the Cr(III) deposited on the zinc surface significantly decrease and thinner Chromate films with an even surface, good decorative appearance and high corrosion resistance are formed Decorative blue-bright Cr(VI)-free films with a slight iridescent tint, obtained in solution, containing Cr(III) nitrate (0.2), malonic acid (0.3) and Co(II) nitrate (0.02) mol dm^?3, at p H 1.6-2.0 at room temperature over 30–60 s, possess corrosion resistance (192–240 h in a salt spray chamber) similar to that of iridescent Chromate films, obtained in acidic Cr(VI) solution.     

Investigating Immune Responses to the scAAV9-HEXM Gene Therapy Treatment in Tay–Sachs Disease and Sandhoff Disease Mouse Models

GM2 gangliosidosis disorders are a group of neurodegenerative diseases that result from a functional deficiency of the enzyme β-hexosaminidase A (HexA). HexA consists of an α- and β-subunit; a deficiency in either subunit results in Tay–Sachs Disease (TSD) or Sandhoff Disease (SD), respectively. Viral vector gene transfer is viewed as a potential method of treating these diseases. A recently constructed isoenzyme to HexA, called HexM, has the ability to effectively catabolize GM2 gangliosides in vivo. Previous gene transfer studies have revealed that the scAAV9-HEXM treatment can improve survival in the murine SD model. However, it is speculated that this treatment could elicit an immune response to the carrier capsid and “non-self”-expressed transgene. This study was designed to assess the immunocompetence of TSD and SD mice, and test the immune response to the scAAV9-HEXM gene transfer. HexM vector-treated mice developed a significant anti-HexM T cell response and antibody response. This study confirms that TSD and SD mouse models are immunocompetent, and that gene transfer expression can create an immune response in these mice. These mouse models could be utilized for investigating methods of mitigating immune responses to gene transfer-expressed “non-self” proteins, and potentially improve treatment efficacy.