Changes in retinoic acid receptor status, 5′-deiodinase activity and neuroendocrine response to voluntary wheel running

Little information is available on the involvement of retinoic acid in processes related to physical activity. The aim of this study was to test the hypotheses that long-term voluntary wheel running (1) modifies RARs concentration as well as the expression of RAR subtypes and (2) alters I iodothyronine deiodinase (5′-DI) activity in rat liver. To evaluate relevant mechanisms, hepatic gene expression of specific nuclear receptor coregulators and stress hormone levels in plasma have also been measured. Sprague-Dawley rats were housed either in standard cages or in cages with access to running wheel attached for 3 weeks. RAR maximal binding capacity in the liver was found to be significantly lower while gene expression of RARβ increased in rats exposed to voluntary running compared to that in sedentary controls. Gene expression of RARα, RXRα and RXRβ was found to be unaffected. Voluntary running led to a significant decrease of 5′-DI activity in the liver. No significant changes in the gene expression of specific nuclear receptor coregulators in the liver were observed. Significant elevation of aldosterone while no changes in ACTH and corticosterone concentrations were observed in rats exposed to wheel running compared to those in controls. In conclusion, this study provided first evidence on the reduction of liver RAR concentrations and 5′-DI activity in response to long-term voluntary wheel running. Neuroendocrine mechanisms involved in these changes may include adrenal mineralo- and glucocorticoids.     

Cationic solid lipid nanoparticles (cSLN): structure, stability and DNA binding capacity correlation studies

Cationic solid lipid nanoparticles (cSLN) are promising lipid nanocarriers for intracellular gene delivery based on well-known and widely accepted materials. cSLN containing single-chained cationic lipid cetyltrimethylammonium bromide were produced by high pressure homogenization and characterized in terms of (a) particle size distribution by photon correlation spectroscopy (PCS) and laser diffractometry (LD), (b) thermal behaviour using differential scanning calorimetry (DSC) and (c) the presence of various polymorphic phases was confirmed by X-ray diffraction (WAXD). SLN composed of Imwitor 900P™ (IMW) showed different pDNA stability and binding capacity in comparison to those of Compritol 888 ATO™ (COM). IMW-SLN, having z-ave = 138-157 nm and d(0.5) = 0.15-0.158 μm could maintain this size for 14 days at room temperature. COM-SLN had z-ave = 334 nm and d(0.5) = 0.42 μm on the day of production and could maintain similar size during 90 days. IMW-SLN revealed improved pDNA binding capacity. We attempted to explain these differences by different interactions between the solid lipid and the tested cationic lipid.     

Modified Rose Bengal assay for surface hydrophobicity evaluation of cationic solid lipid nanoparticles (cSLN)

Surface hydrophobicity of nanocarriers influences protein binding and subsequently fate of nanoparticles in blood circulation. Therefore, characterization of surface hydrophobicity of nanocarriers provides important preclinical information. Here, a modified classical adsorption method for the needs of characterization of cationic solid lipid nanoparticles (cSLN) was developed. We have identified possible method limitations that should be considered when performing the analysis, i.e. the problems associated with particle separation from the dispersion and their own absorbance in visible spectrum. We propose two modified methods for performing the assay overcoming the stated limitations. We also discuss here evaluation by different approaches (calculation of binding constants or partitioning quotient) and their suitability for the prepared cSLN formulation. Overall, we confirmed that our modified adsorption method can provide useful information about surface properties of (cationic) SLN, however, performing and evaluation of the assay need special attention in order to obtain the desired results.     

Key production parameters for the development of solid lipid nanoparticles by high shear homogenization

In this work, we report the development and optimization of solid lipid nanoparticles (SLN) production by a simple, fast, and cost-effective high shear homogenization process. A screening of several solid lipids (Compritol 888 ATO, Precirol ATO 5, Cetyl Palmitate, Dynasan 118, Imwitor 900K, Stearic acid) has been carried out in combination with Poloxamer 188 as the selected surfactant, based on the mean particle size and polydispersity index. The improvement of the physical stability of the SLN dispersions was achieved by the use of a cationic lipid (cetyl trimethylammonium bromide) reaching zeta potential values above +60 mV. Combining the optimized speed and time of shear, monodispersed SLN (PdI < 0.25) under the nanometer range could be produced.     

The role of angiotensin type 1 receptor in inflammation and endothelial dysfunction

Endothelial dysfunction plays an important role in all stages of atherosclerosis, and is characterized by an increased activity of vasoconstricting factors, proinflammatory and prothrombotic mediators. The aim of the review is to evaluate the role of angiotensin II (Ang II) and especially of angiotensin type 1 (AT1) receptor in inflammation and endothelial dysfunction. Ang II with AT(1) receptor are through several mechanisms implicated in the progression of atherosclerosis. Stimulation of AT(1) receptor increases oxidative stress especially through activation of NADH/NADPH oxidase in the vascular cells. Oxidative stress is associated with activation of the inflammatory processes. Ang II via AT(1) receptor increases expression of adhesion molecules and stimulates the induction of monocyte chemoattractant protein-1 (MCP-1). AT(1) receptor enhances the activation of nuclear factor NF-kappaB, which stimulates the production of proinflammatory cytokines. Proinflammatory cytokines on the other side may induce acute-phase response in the liver. Activation of AT(1) receptor via inducible cyclooxygenase (COX)-2 promotes biosynthesis of matrix metalloproteinases (MMPs). Ang II is implicated in the process of angiogenesis. Via AT(1) receptor takes part in the regulation of vascular endothelial growth factor (VEGF), which is one of the most angiogenic factors and stimulates the activity of endothelial progenitor cells (EPC). Recently some patents were reported discussing role of different compounds for the treatment of cardiovascular disease, renovascular disease nephropathy, peripheral vascular disease, portal hypertension and ophthalmic disorders, are cyclooxygenase-2 inhibitors.     

Comet assay reveals no genotoxicity risk of cationic solid lipid nanoparticles

Cationic solid lipid nanoparticles (cSLN) are colloidal carriers for genes or drugs, particularly lipophilic drugs. Several reports exist on their high efficiency, but only a few studies report the effect of cSLNs on living cells. In the present work, internalization, cell viability (alamar blue assay) and genotoxic potential (alkaline comet assay) of three cSLN formulations (A–C) were evaluated in HepG2 and Caco‐2 cells. cSLN showed an average hydrodynamic diameter (z‐ave) of 141–222 nm, zeta‐potential of 55.0–72.5 mV and polidispersity indices (PdI) of 0.336–0.421. Dispersion in physiological buffers increased z‐ave and PdI. 0.01 mg ml^–1 cSLN unaffected cell viability, but 1.0 mg ml^–1 significantly decreased it, being cSLN‐C (Compritol‐based) the most toxic and HepG2 the most affected. DNA damage was not significantly increased by 0.1 mg ml^–1 cSLN but damage was observed at 1.0 mg ml^–1 cSLN‐C. Thus, no genotoxicity is to be expected at concentrations that do not reduce cell viability. Copyright © 2013 John Wiley & Sons, Ltd.     

The therapeutic effect of B-type natriuretic peptides in acute decompensated heart failure

B-type natriuretic peptide (BNP) exhibits roles in natriuresis and diuresis, making it an ideal drug that may aid in diuresing a fluid-overloaded patient with poor or worsening renal function. Several randomized clinical trials have tested the hypothesis that infusions of pharmacological doses of BNP to acute heart failure (HF) patients may enhance decongestion and preserve renal function in this clinical setting. Unfortunately, none of these have demonstrated beneficial outcomes. The current challenge for BNP research in acute HF lies in addressing a failure of concept and a reluctance to abandon an ineffective research model. Future success will necessitate a detailed understanding of the mechanism of action of BNP, as well as better integration of basic and clinical science.