Silicon in prevention of atherosclerosis and other age-related diseases.

Researchers' interest in silicon as an element important for the functioning of the animal and human body began in the 1970s. Soluble compounds of silicon bioavailable from water and food seem to have important meaning for life processes occurring in the body. So far, researchers have focused on the significance of silicon for the development of bones and connective tissue, and its role in preventing neurodegenerative diseases and atherosclerosis. Despite numerous studies, the role of silicon as an active element in the human body is poorly understood. Since the involvement of lipid oxidation and inflammatory processes in the pathogenesis of atherosclerosis is well known, this article summarizes and discusses the current research and scientific observations regarding silicon, primarily in terms of its beneficial influence on redox and anti-inflammatory reactions and the lipid profile. The association of silicon with the stabilization of the structure of glycosaminoglycans and their protein complexes may also support the anti-atherosclerotic effect. The authors attempted to collect and present existing publications that could confirm the beneficial role of dietary silicon in the prevention of age-related diseases and explain the potential mechanisms of its action.

Discovery of 5-{2-[5-Chloro-2-(5-ethoxyquinoline-8-sulfonamido)phenyl]ethynyl}-4-methoxypyridine-2-carboxylic Acid, a Highly Selective in Vivo Useable Chemical Probe to Dissect MCT4 Biology.

Due to increased lactate production during glucose metabolism, tumor cells heavily rely on efficient lactate transport to avoid intracellular lactate accumulation and acidification. Monocarboxylate transporter 4 (MCT4/SLC16A3) is a lactate transporter that plays a central role in tumor pH modulation. The discovery and optimization of a novel class of MCT4 inhibitors (hit 9a), identified by a cellular screening in MDA-MB-231, is described. Direct target interaction of the optimized compound 18n with the cytosolic domain of MCT4 was shown after solubilization of the GFP-tagged transporter by fluorescence cross-correlation spectroscopy and microscopic studies. In vitro treatment with 18n resulted in lactate efflux inhibition and reduction of cellular viability in MCT4 high expressing cells. Moreover, pharmacokinetic properties of 18n allowed assessment of lactate modulation and antitumor activity in a mouse tumor model. Thus, 18n represents a valuable tool for investigating selective MCT4 inhibition and its effect on tumor biology.

Microvascular damage - a marker of specific organ involvement in mixed connective tissue disease?

Mixed connective tissue disease (MCTD) is a complex entity, which incorporates features of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc) and polymyositis/dermatomyositis (PM/DM). Nailfold videocapillaroscopy (NVC) is a simple, safe and non-invasive technique of capillary vessel assessment, allowing for qualitative and quantitative assessment of microcirculation. NVC plays a pivotal role in the diagnostic algorithm of connective tissue diseases, especially in systemic sclerosis (SSc). Numerous studies have shown a correlation between organ involvement and disease progression in SSc. In the current literature, there are limited data on relationship between NVC and organ involvement in MCTD patients. In the present article the relevant literature describing NVC examination in patients with MCTD and comparisons with some clinical situations are discussed.

Metal Ions Supported Porous Coatings by Using AC Plasma Electrolytic Oxidation Processing.

Coatings enriched with zinc and copper as well as calcium or magnesium, fabricated on titanium substrate by Plasma Electrolytic Oxidation (PEO) under AC conditions (two cathodic voltages, i.e., -35 or -135 V, and anodic voltage of +400 V), were investigated. In all experiments, the electrolytes were based on concentrated orthophosphoric acid (85 wt%) and zinc, copper, calcium and/or magnesium nitrates. It was found that the introduced calcium and magnesium were in the ranges 5.0-5.4 at% and 5.6-6.5 at%, respectively, while the zinc and copper amounts were in the range of 0.3-0.6 at%. Additionally, it was noted that the metals of the block S (Ca and Mg) could be incorporated into the structure about 13 times more than metals of the transition group (Zn and Cu). The incorporated metals (from the electrolyte) into the top-layer of PEO phosphate coatings were on their first (Cu+) or second (Cu2+, Ca2+ and Mg2+) oxidation states. The crystalline phases (TiO and Ti3O) were detected only in coatings fabricated at cathodic voltage of -135 V. It has also been pointed that fabricated porous calcium-phosphate coatings enriched with biocompatible magnesium as well as with antibacterial zinc and copper are dedicated mainly to medical applications. However, their use for other applications (e.g., catalysis and photocatalysis) after additional functionalizations is not excluded.

Phosphate Porous Coatings Enriched with Selected Elements via PEO Treatment on Titanium and Its Alloys: A Review.

This paper shows that the subject of porous coatings fabrication by Plasma Electrolytic Oxidation (PEO), known also as Micro Arc Oxidation (MAO), is still current, inter alia because metals and alloys, which can be treated by the PEO method, for example, titanium, niobium, tantalum and their alloys, are increasingly available for sale. On the international market, apart from scientific works/activity developed at universities, scientific research on the PEO coatings is also underway in companies such as Keronite (Great Britain), Magoxid-Coat (Germany), Mofratech (France), Machaon (Russia), as well as CeraFuse, Tagnite, Microplasmic (USA). In addition, it should be noted that the development of the space industry and implantology will force the production of trouble-free micro- and macro-machines with very high durability. Another aspect in favor of this technique is the rate of part treatment, which does not exceed several dozen minutes, and usually only lasts a few minutes. Another advantage is functionalization of fabricated surface through thermal or hydrothermal modification of fabricated coatings, or other methods (Physical vapor deposition (PVD), chemical vapor deposition (CVD), sol-gel), including also reoxidation by PEO treatment in another electrolyte. In the following chapters, coatings obtained both in aqueous solutions and electrolytes based on orthophosphoric acid will be presented; therein, dependent on the PEO treatment and the electrolyte used, they are characterized by different properties associated with their subsequent use. The possibilities for using coatings produced by means of plasma electrolytic oxidation are very wide, beginning from various types of catalysts, gas sensors, to biocompatible and antibacterial coatings, as well as hard wear coatings used in machine parts, among others, used in the aviation and aerospace industries.

Phosphate Coatings Enriched with Copper on Titanium Substrate Fabricated Via DC-PEO Process.

The present paper covers the possible ways to fabricate advanced porous coatings that are enriched in copper on a titanium substrate through Direct Current Plasma Electrolytic Oxidation (DC-PEO) with voltage control, in electrolytes made of concentrated orthophosphoric acid with the addition of copper(II) nitrate(V) trihydrate. In these studies, solutions containing from 0 to 650 g salt per 1 dm3 of acid and anodic voltages from 450 V up to 650 V were used. The obtained coatings featuring variable porosity could be best defined by the three-dimensional (3D) parameter Sz, which lies in the range 9.72 to 45.18 µm. The use of copper(II) nitrate(V) trihydrate in the electrolyte, resulted, for all cases, in the incorporation of the two oxidation forms, i.e., Cu+ and Cu2+ into the coatings. Detailed X-Ray Photoelectron Spectroscopy (XPS) studies layers allowed for stating that the percentage of copper in the surface layer of the obtained coatings was in the range of 0.24 at% to 2.59 at%. The X-Ray Diffraction (XRD) studies showed the presence of copper (α-Cu2P2O7, and Cu3(PO4)2) and titanium (TiO2-anatase, TiO3, TiP2O7, and Ti0.73O0.91) compounds in coatings. From Energy-Dispersive X-Ray Spectroscopy (EDS) and XPS studies, it was found that the Cu/P ratio increases with the increase of voltage and the amount of salt in the electrolyte. The depth profile analysis by Glow-Discharge Optical Emission Spectroscopy (GDOES) method showed that a three-layer model consisting of a top porous layer, a semi-porous layer, and a transient/barrier layer might describe the fabricated coatings.

Porous Coatings Containing Copper and Phosphorus Obtained by Plasma Electrolytic Oxidation of Titanium.

To fabricate porous copper coatings on titanium, we used the process of plasma electrolytic oxidation (PEO) with voltage control. For all experiments, the three-phase step-up transformer with six-diode Graetz bridge was used. The voltage and the amount of salt used in the electrolyte were determined so as to obtain porous coatings. Within the framework of this study, the PEO process was carried out at a voltage of 450 VRMS in four electrolytes containing the salt as copper(II) nitrate(V) trihydrate. Moreover, we showed that the content of salt in the electrolyte needed to obtain a porous PEO coating was in the range 300-600 g/dm3. After exceeding this amount of salts in the electrolyte, some inclusions on the sample surface were observed. It is worth noting that this limitation of the amount of salts in the electrolyte was not connected with the maximum solubility of copper(II) nitrate(V) trihydrate in the concentrated (85%) orthophosphoric acid. To characterize the obtained coatings, numerous techniques were used. In this work, we used scanning electron microscopy (SEM) coupled with electron-dispersive X-ray spectroscopy (EDS), conducted surface analysis using confocal laser scanning microscopy (CLSM), and studied the surface layer chemical composition of the obtained coatings by X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), glow discharge of optical emission spectroscopy (GDOES), and biological tests. It was found that the higher the concentration of Cu(NO3)2∙3H2O in the electrolyte, the higher the roughness of the coatings, which may be described by 3D roughness parameters, such as Sa (1.17-1.90 µm) and Sp (7.62-13.91 µm). The thicknesses of PEO coatings obtained in the electrolyte with 300-600 g/dm3 Cu(NO3) 2∙3H2O were in the range 7.8 to 10 µm. The Cu/P ratio of the whole volume of coating measured by EDS was in the range 0.05-0.12, while the range for the top layer (measured using XPS) was 0.17-0.24. The atomic concentration of copper (0.54-0.72 at%) resulted in antibacterial and fungicidal properties in the fabricated coatings, which can be dedicated to biocompatible applications.

Synthesis of amide and sulfonamide substituted N-aryl 6-aminoquinoxalines as PFKFB3 inhibitors with improved physicochemical properties.

In oncology, the "Warburg effect" describes the elevated production of energy by glycolysis in cancer cells. The ubiquitous and hypoxia-induced 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) plays a noteworthy role in the regulation of glycolysis by producing fructose-2,6-biphosphate (F-2,6-BP), a potent activator of the glycolysis rate-limiting phosphofructokinase PFK-1. Series of amides and sulfonamides derivatives based on a N-aryl 6-aminoquinoxaline scaffold were synthesized and tested for their inhibition of PFKFB3 in vitro in a biochemical assay as well as in HCT116 cells. The carboxamide series displayed satisfactory kinetic solubility and metabolic stability, and within this class, potent lead compounds with low nanomolar activity have been identified with a suitable profile for further in vivo evaluation.

Discovery and Structure-Activity Relationships of N-Aryl 6-Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors.

Energy and biomass production in cancer cells are largely supported by aerobic glycolysis in what is called the Warburg effect. The process is regulated by key enzymes, among which phosphofructokinase PFK-2 plays a significant role by producing fructose-2,6-biphosphate; the most potent activator of the glycolysis rate-limiting step performed by phosphofructokinase PFK-1. Herein, the synthesis, biological evaluation and structure-activity relationship of novel inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), which is the ubiquitous and hypoxia-induced isoform of PFK-2, are reported. X-ray crystallography and docking were instrumental in the design and optimisation of a series of N-aryl 6-aminoquinoxalines. The most potent representative, N-(4-methanesulfonylpyridin-3-yl)-8-(3-methyl-1-benzothiophen-5-yl)quinoxalin-6-amine, displayed an IC50 of 14 nm for the target and an IC50 of 0.49 µm for fructose-2,6-biphosphate production in human colon carcinoma HCT116 cells. This work provides a new entry in the field of PFKFB3 inhibitors with potential for development in oncology.

Novel Porous Phosphorus⁻Calcium⁻Magnesium Coatings on Titanium with Copper or Zinc Obtained by DC Plasma Electrolytic Oxidation: Fabrication and Characterization.

In this paper, the characteristics of new porous coatings fabricated at three voltages in electrolytes based on H3PO4 with calcium nitrate tetrahydrate, magnesium nitrate hexahydrate, and copper(II) nitrate trihydrate are presented. The SEM, energy dispersive spectroscopy (EDS), glow discharge optical emission spectroscopy (GDOES), X-ray photoelectron spectroscopy (XPS), and XRD techniques for coating identification were used. It was found that the higher the plasma electrolytic oxidation (PEO) (micro arc oxidation (MAO)) voltage, the thicker the porous coating with higher amounts of built-in elements coming from the electrolyte and more amorphous phase with signals from crystalline Ca(H2PO4)2∙H2O and/or Ti(HPO4)2∙H2O. Additionally, the external parts of the obtained porous coatings formed on titanium consisted mainly of Ti4+, Ca2+, Mg2+ and PO43-, HPO42-, H2PO4-, P2O74- as well as Zn2+ or copper Cu⁺/Cu2+. The surface should be characterized by high biocompatibility, due to the presence of structures based on calcium and phosphates, and have bactericidal properties, due to the presence of zinc and copper ions. Furthermore, the addition of magnesium ions should accelerate the healing of postoperative wounds, which could lead to faster patient recovery.

SEM, EDS and XPS Analysis of the Coatings Obtained on Titanium after Plasma Electrolytic Oxidation in Electrolytes Containing Copper Nitrate.

In the paper, the Scanning Electron Microscopy (SEM) with Energy Dispersive X-ray Spectroscopy (EDS) and X-ray Photoelectron Spectroscopy (XPS) results of the surface layer formed on pure titanium after plasma electrolytic oxidation (micro arc oxidation) at the voltage of 450 V are shown. As an electrolyte, the mixture of copper nitrate Cu(NO3)2 (10-600 g/L) in concentrated phosphoric acid H3PO4 (98 g/mol) was used. The thickness of the obtained porous surface layer equals about 10 µm, and it consists mainly of titanium phosphates and oxygen with embedded copper ions as a bactericidal agent. The maximum percent of copper in the PEO surface layer was equal to 12.2 ± 0.7 wt % (7.6 ± 0.5 at %), which is the best result that the authors obtained. The top surface layer of all obtained plasma electrolytic oxidation (PEO) coatings consisted most likely mainly of Ti3(PO4)4∙nH3PO4 and Cu3(PO4)2∙nH3PO4 with a small addition of CuP2, CuO and Cu2O.

Classification of video sequences into chosen generalized use classes of target size and lighting level.

The VQiPS (Video Quality in Public Safety) Working Group, supported by the U.S. Department of Homeland Security, has been developing a user guide for public safety video applications. According to VQiPS, five parameters have particular importance influencing the ability to achieve a recognition task. They are: usage time-frame, discrimination level, target size, lighting level, and level of motion. These parameters form what are referred to as Generalized Use Classes (GUCs). The aim of our research was to develop algorithms that would automatically assist classification of input sequences into one of the GUCs. Target size and lighting level parameters were approached. The experiment described reveals the experts' ambiguity and hesitation during the manual target size determination process. However, the automatic methods developed for target size classification make it possible to determine GUC parameters with 70 % compliance to the end-users' opinion. Lighting levels of the entire sequence can be classified with an efficiency reaching 93 %. To make the algorithms available for use, a test application has been developed. It is able to process video files and display classification results, the user interface being very simple and requiring only minimal user interaction.

Chelate Ring Size Effect as a Factor of Selective Fluorescent Recognition of Zn(2+) Ions by Pyrrolo[2,3-b]quinoxaline with a Substituted 2-Pyridyl Group Receptor.

Analysis of the spectral properties and structural differences of two turn-on ratiometric fluorescent receptors for Zn(2+) and Cd(2+) ions, derivatives of pyrrolo[2,3-b]quinoxaline (2), and earlier published 3 (Ostrowska et al. CrystEngComm 2015, 17, 498-502) was performed. Both ligands are E/Z push-pull olefins interconverting at room temperature, with barriers to rotation about enamine double bonds, from E to Z isomers of 19.3 ± 0.1 and 16.9 ± 0.3 kcal/mol and from Z to E of 16.9 ± 0.3 and 15.7 ± 0.2 kcal/mol, respectively. Diastereoisomers (E)-2 and (Z)-2 were isolated and characterized by X-ray structural analysis. The formation of complexes by (E/Z)-2 with acetates and acetylacetonates of Zn(2+) and Cd(2+) was monitored by UV-vis, fluorescence, and (1)H NMR titrations in acetonitrile, respectively. X-ray structural analysis for isolated [(E)-2]2Zn in relation to earlier published (E)-3-ZnOAc revealed the formation of a six-coordinated zinc ion with six- and four-membered bis-chelate rings by (E)-2. The chelate effect increases the ligand affinity for Zn(2+) (log ß12 = 12.45) and causes the elongation of nitrogen-metal bonds. Extension of the coordination cavity size allows coordination of a cadmium ion. The introduction of a flexible ethylene linker between the fluorophore and ionophore pyridyl groups in 3 significantly affects the selectivity of zinc-ion recognition. The distorted tetrahedral geometry of (E)-3-ZnOAc with a four-coordinated zinc ion appears to be the most preferred because of the short donor-zinc distance with a 1:1 binding mode. The formation of the small coordination cavity size with six-membered bis-chelate rings provides an effective overlap of zinc and donor orbitals, precluding the coordination of a cadmium ion in the same manner as zinc.

Molecular recognition of AT-DNA sequences by the induced CD pattern of dibenzotetraaza[14]annulene (DBTAA)-adenine derivatives.

An investigation of the interactions of two novel and several known DBTAA-adenine conjugates with double-stranded DNA and RNA has revealed the DNA/RNA groove as the dominant binding site, which is in contrast to the majority of previously studied DBTAA analogues (DNA/RNA intercalators). Only DBTAA-propyladenine conjugates revealed the molecular recognition of AT-DNA by an ICD band pattern > 300 nm, whereas significant ICD bands did not appear for other ds-DNA/RNA. A structure-activity relation for the studied series of compounds showed that the essential structural features for the ICD recognition are a) the presence of DNA-binding appendages (adenine side chain and positively charged side chain) on both DBTAA side chains, and b) the presence of a short propyl linker, which does not support intramolecular aromatic stacking between DBTAA and adenine. The observed AT-DNA-ICD pattern differs from previously reported ss-DNA (poly dT) ICD recognition by a strong negative ICD band at 350 nm, which allows for the dynamic differentiation between ss-DNA (poly dT) and coupled ds-AT-DNA.

Dibenzotetraaza[14]annulene-adenine conjugate recognizes complementary poly dT among ss-DNA/ss-RNA sequences.

Among three novel DBTAA derivatives only the DBTAA-propyl-adenine conjugate showed recognition of the consecutive oligo dT sequence by increased affinity and specific induced chirooptical response in comparison to other single stranded RNA and DNA; whereby of particular importance is the up until now unique efficient differentiation between dT and rU. At variance, its close analogue DBTAA-hexyl-adenine did not reveal any selectivity between ss-DNA/RNA pointing out the important role of steric factors (linker length); moreover non-selectivity of the reference compound (, lacking adenine) stressed the importance of adenine interactions in the selectivity.