S-Ribosylhomocysteine analogues modified at the ribosyl C-4 position

4-C-Alkyl/aryl-S-ribosylhomocysteine (SRH) analogues were prepared by coupling of homocysteine with 4-substituted ribofuranose derivatives. The diastereoselective incorporation of the methyl substituent into the 4 position of the ribose ring was accomplished by the addition of methylmagnesium bromide to the protected ribitol-4-ulose yielding the 4-C-methylribitol in 85% yield as single 4R diastereomer. The 4-C hexyl, octyl, vinyl, and aryl ribitols were prepared analogously. Chelation controlled addition of a carbanion to ketones from the Si-face was responsible for the observed stereochemical outcome. Oxidation of the primary alcohol of the 4-C ribitols with catalytic amounts of tetrapropylammonium perruthenate in the presence of N-methylmorpholine N-oxide produced 4-C-alkylribono-1,4-lactones in high yields. Mesylation of the latter compounds at the 5-hydroxyl position and treatment with a protected homocysteine thiolate afforded protected 4-C-alkyl/aryl-SRH analogues as the lactones. Reduction with lithium triethylborohydride and successive global deprotections with TFA afforded 4-C-alkyl/aryl SRH analogues. These analogues might impede the S-ribosylhomocysteinase(LuxS)-catalyzed reaction by preventing β-elimination of a homocysteine molecule, and thus depleting the production of quorum sensing signaling molecule AI-2.     

Anti-Inflammatory Effect of Very High Dose Local Vessel Wall Statin Administration: Poly(L,L-Lactide) Biodegradable Microspheres with Simvastatin for Drug Delivery System (DDS)

Atherosclerosis involves an ongoing inflammatory response of the vascular endothelium and vessel wall of the aorta and vein. The pleiotropic effects of statins have been well described in many in vitro and in vivo studies, but these effects are difficult to achieve in clinical practice due to the low bioavailability of statins and their first-pass metabolism in the liver. The aim of this study was to test a vessel wall local drug delivery system (DDS) using PLA microstructures loaded with simvastatin. Wistar rats were fed high cholesterol chow as a model. The rat vessels were chemically injured by repeated injections of perivascular paclitaxel and 5-fluorouracil. The vessels were then cultured and treated by the injection of several concentrations of poly(L,L-lactide) microparticles loaded with the high local HMG-CoA inhibitor simvastatin (0.58 mg/kg) concentration (SVPLA). Histopathological examinations of the harvested vessels and vital organs after 24 h, 7 days and 4 weeks were performed. Microcirculation in mice as an additional test was performed to demonstrate the safety of this approach. A single dose of SVPLA microspheres with an average diameter of 6.4 μm and a drug concentration equal to 8.1% of particles limited the inflammatory reaction of the endothelium and vessel wall and had no influence on microcirculation in vivo or in vitro. A potent pleiotropic (anti-inflammatory) effect of simvastatin after local SVPLA administration was observed. Moreover, significant concentrations of free simvastatin were observed in the vessel wall (compared to the maximum serum level). In addition, it appeared that simvastatin, once locally administered as SVPLA particles, exerted potent pleiotropic effects on chemically injured vessels and presented anti-inflammatory action. Presumably, this effect was due to the high local concentrations of simvastatin. No local or systemic side effects were observed. This approach could be useful for local simvastatin DDSs when high, local drug concentrations are difficult to obtain, or systemic side effects are present.     

Effects of Osthole on Inflammatory Gene Expression and Cytokine Secretion in Histamine-Induced Inflammation in the Caco-2 Cell Line

Hyperactivity of the immune system in the gastrointestinal tract leads to the development of chronic, inflammation-associated disorders. Such diseases, including inflammatory bowel disease, are not completely curable, but the specific line of treatment may reduce its symptoms. However, the response to treatment varies among patients, creating a necessity to uncover the pathophysiological basis of immune-mediated diseases and apply novel therapeutic strategies. The present study describes the anti-inflammatory properties of osthole during histamine-induced inflammation in the intestinal Caco-2 cell line. Osthole reduced the secretion of cytokines (CKs) and the expression level of inflammation-associated genes, which were increased after a histamine treatment. We have shown that the secretion of pro-inflammatory CKs (IL-1β, IL-6, IL-8, and TNF-α) during inflammation may be mediated by NFκB, and, after osthole treatment, this signaling pathway was disrupted. Our results suggest a possible role for osthole in the protection against inflammation in the gastrointestinal tract; thus, osthole may be considered as an anti-inflammatory modulator.     

Reversal Activity and Toxicity of Heparin-Binding Copolymer after Subcutaneous Administration of Enoxaparin in Mice

Uncontrolled bleeding after enoxaparin (ENX) is rare but may be life-threatening. The only registered antidote for ENX, protamine sulfate (PS), has 60% efficacy and can cause severe adverse side effects. We developed a diblock copolymer, heparin-binding copolymer (HBC), that reverses intravenously administered heparins. Here, we focused on the HBC inhibitory activity against subcutaneously administered ENX in healthy mice. BALB/c mice were subcutaneously injected with ENX at the dose of 5 mg/kg. After 110 min, vehicle, HBC (6.25 and 12.5 mg/kg), or PS (5 and 10 mg/kg) were administered into the tail vein. The blood was collected after 3, 10, 60, 120, 360, and 600 min after vehicle, HBC, or PS administration. The activities of antifactors Xa and IIa and biochemical parameters were measured. The main organs were collected for histological analysis. HBC at the lower dose reversed the effect of ENX on antifactor Xa activity for 10 min after antidote administration, whereas at the higher dose, HBC reversed the effect on antifactor Xa activity throughout the course of the experiment. Both doses of HBC completely reversed the effect of ENX on antifactor IIa activity. PS did not reverse antifactor Xa activity and partially reversed antifactor IIa activity. HBC modulated biochemical parameters. Histopathological analysis showed changes in the liver, lungs, and spleen of mice treated with HBC and in the lungs and heart of mice treated with PS. HBC administered in an appropriate dose might be an efficient substitute for PS to reverse significantly increased anticoagulant activity that may be connected with major bleeding in patients receiving ENX subcutaneously.     

Effect of the sintering temperature on microstructure and properties of Al2O3–Cu–Ni hybrid composites obtained by PPS

In the present research, the influence of sintering temperature on the microstructure and properties of Al₂O₃–Cu–Ni hybrid composites prepared by the Pulse Plasma Sintering (PPS) technique were described. In this research, three temperatures have been selected: 1250°C, 1300°C, and 1350°C. SEM observations were carried out to determine the distribution of the metallic phase in the composite depending on the sintering temperature. The conducted experiments and microscopic observations enabled a better understanding of the phenomena occurring between the ceramic matrix and metallic phase in the obtained materials. The mechanical properties like a hardness and fracture toughness were measured. The technology applied allowed us to obtain ceramic-metal composites with a homogeneous microstructure. It was found that the sintering temperature influences the selected physical and mechanical properties of the composites produced. It was found that samples produced at 1300°C are characterized by the highest relative density and the mechanical properties.     

Dipeptides of S-Substituted Dehydrocysteine as Artzyme Building Blocks: Synthesis,Complexing Abilities and Antiproliferative Properties

Background: Dehydropeptides are analogs of peptides containing at least one conjugate double bond between α,β-carbon atoms. Its presence provides unique structural properties and reaction centre for chemical modification. In this study, the series of new class of dipeptides containing S-substituted dehydrocysteine with variety of heterocyclic moieties was prepared. The compounds were designed as the building blocks for the construction of artificial metalloenzymes (artzymes). Therefore, the complexing properties of representative compounds were also evaluated. Furthermore, the acknowledged biological activity of natural dehydropeptides was the reason to extend the study for antiproliferative action of against several cancer cell lines. Methods: The synthetic strategy involves glycyl and phenylalanyl-(Z)-β-bromodehydroalanine as a substrate in one pot addition/elimination reaction of thiols. After deprotection of N-terminal amino group the compounds with triazole ring were tested as complexones for copper(II) ions using potentiometric titration and spectroscopic techniques (UV-Vis, CD, EPR). Finally, the antiproliferative activity was evaluated by sulforhodamine B assay. Results and Conclusions: A simple and efficient procedure for preparation of dipeptides containing S-substituded dehydrocysteine was provided. The peptides containing triazole appeared to be strong complexones of copper(II) ions. Some of the peptides exhibited promising antiproliferative activities against number of cancer cell lines, including cell lines resistant to widely used anticancer agent.     

The Causes and Potential Injurious Effects of Elevated Serum Leptin Levels in Chronic Kidney Disease Patients

Leptin is an adipokine that regulates appetite and body mass and has many other pleiotropic functions, including regulating kidney function. Increased evidence shows that chronic kidney disease (CKD) is associated with hyperleptinemia, but the reasons for this phenomenon are not fully understood. In this review, we focused on potential causes of hyperleptinemia in patients with CKD and the effects of elevated serum leptin levels on patient kidney function and cardiovascular risk. The available data indicate that the increased concentration of leptin in the blood of CKD patients may result from both decreased leptin elimination from the circulation by the kidneys (due to renal dysfunction) and increased leptin production by the adipose tissue. The overproduction of leptin by the adipose tissue could result from: (a) hyperinsulinemia; (b) chronic inflammation; and (c) significant lipid disturbances in CKD patients. Elevated leptin in CKD patients may further deteriorate kidney function and lead to increased cardiovascular risk.     

Determination of the Initiating Capability of Detonators Containing TKX‐50, MAD‐X1, PETNC,DAAF, RDX,HMX or PETN as a Base Charge,by Underwater Explosion Test

A comprehensive investigation to determine the initiation power of detonators containing as a base charge the novel explosives: dihydroxylammonium 5,5′‐bis(tetrazolate‐1N‐oxide) – TKX‐50, dihydroxylammonium 5,5′‐bis(3‐nitro‐1,2,4‐triazolate‐1N‐oxide) – MAD‐X1, pentaerythritol tetranitrocarbamate – PETNC and 3,3′‐diamino‐4,4′‐azoxyfurazan – DAAF in comparison with RDX, HMX and PETN was undertaken. In order to estimate the initiation power of the detonators, the underwater initiating capability test was used. The total energy as a sum of the primary shock wave energy and the bubble gas energy was determined for each of these explosives, by measuring the overpressure of the shock waves generated in water. Moreover, the complete synthesis for novel explosives is presented. The thermal behavior of the explosives was investigated using DSC (differential scanning calorimetry). The gas phase absolute molar enthalpies at 298 K and 10⁵ Pa were calculated theoretically using the modified complete basis set method (CBS‐4M; M referring to the use of minimal population localization) with the Gaussian 09 software. Gas phase standard molar enthalpies of formation (ΔH_f°_(g)) at 298 K were computed using the atomization energy method. Standard molar enthalpies of formation (▵H_(s)°) were calculated using ΔH_f°_(g) and the standard molar enthalpies of sublimation by applying Trouton’s rule. The Chapman‐Jouguet (CJ) characteristics based on calculated ▵H_(s)° values were computed using the EXPLO5 V6.01 thermochemical computer code. For the calculations the theoretical maximum densities and densities obtained during the experiments presented in this work were used.     

A Comparative Study of Mechanical Properties,Thermal Conductivity,Residual Stresses,and Wear Resistance of Aluminum-Alumina Composites Obtained by Squeeze Casting and Powder Metallurgy

Squeeze casting and powder metallurgy techniques were employed to fabricate AlSi12/Al₂O₃ composites, which are lightweight structural materials with potential applications in the automotive industry. The impact of the processing route on the material properties was studied. Comparative analyses were conducted for the Vickers hardness, flexural strength, fracture toughness, thermal conductivity, thermal residual stresses, and frictional wear. Our results show that the squeeze cast composite exhibits superior properties to those obtained using powder metallurgy.