With the increasing knowledge of the pathogenesis of atherosclerosis, it appears that in the future the prevention of cardiovascular disease will involve not only risk factor correction, but also direct pharmacological control of processes occurring in the arterial wall. Among these, a pivotal role is played by smooth muscle cell (SMC) migration and proliferation, which, together with lipid deposition, are prominent features of atherogenesis and restenosis after angioplasty. Mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are essential for cell growth, hence drugs affecting this metabolic pathway are potential antiatherosclerotic agents. Recently, we provided in vitro and in vivo evidence that fluvastatin, simvastatin and lovastatin, but not pravastatin, decrease SMC migration and proliferation dose dependently, independently of their hypocholesterolemic properties. The in vitro inhibition of cell migration and proliferation induced by simvastatin and fluvastatin (70-90% decrease) was prevented completely by the addition of mevalonate, and partially prevented by farnesol and geranylgeraniol (80%), confirming the specific role of isoprenoid metabolites in regulating these cellular events, probably through prenylated protein(s). The in vivo antiproliferative activity of fluvastatin on neointimal hyperplasia in normocholesterolemic rabbits was also prevented fully by the local delivery of mevalonate, by means of an Alzet pump. Fluvastatin and simvastatin also inhibited cholesterol esterification and deposition induced by acetylated LDL in cultured macrophages. This effect was fully prevented by the addition of mevalonate or geranylgeraniol. Taken together, these results suggest that, beyond their effects on plasma lip-ids, HMG-CoA reductase inhibitors exert a direct antiatherosclerotic effect on the arterial wall, probably through local inhibition of isoprenoid biosynthesis.
This work aims to preliminarily evaluate the reliability of regenerated keratins (RKs) in the design of microparticulate drug delivery systems by studying their processability and cytotoxicity. RKs were extracted by sulfitolysis from wool waste. A 4.5% w/w RK solution was spray‐dried, and microparticles were sterilized by steam vapor under pressure. Scanning electron microscope, sodium dodecyl sulfate‐polyacrylamide gel electrophoresis, and Fourier transform infrared spectroscopy were used to characterize RKs and microparticles thereof. The in vitro cytotoxicity was determined by assessing the release of lactate dehydrogenase in the human monocytic cell line Tamm–Horsfall glycoprotein‐1. RK‐based microparticles with a narrow and unimodal particle size distribution (~6 µm) were obtained. They had a raisin‐like structure with a smooth surface. Both microparticle morphology and RK molecular weight were well‐preserved after sterilization. The curve fitting of the amide I bands showed that RK in the microparticles was prevalently present in the disordered/α‐helix secondary structures which made the protein soluble in water. To promote crystallization in the β‐sheet secondary structure and, therefore, water insolubility, RK‐based microparticles were immersed in an aqueous solution of acetic acid at pH 3.5 overnight. RK did not induce any appreciable cellular cytotoxicity at any of the concentrations (from 1 up to 1000 µg sterile microparticles in 1 ml cell culture medium) or time‐points (24–72 h) tested. These preliminary data suggest the feasibility of producing RK biocompatible microparticles using waste wool as starting material. Copyright © 2013 John Wiley & Sons, Ltd.
-Hydr~xych~~~tero~*~, 25-hy~oxycholesterol and choiesterol suppressed LDL uptake and degradation in human extrahepatic and hepatic cell lines in a concentrationdependent manner. Cholesterol was the least potent, and the inhibitory et&ct of oxysterols was more pronounced in skin fibroblasts and in endothelial cell line EAhy 926 than in hepatoma HepG2 cells. Shorter incubations were required for oxysterols to achieve 50% inhibition of LDL uptake and degradation in all cultured cells. The inhibition of LDL catabolism in extrahepatic cells by 27.hydroxycholesterol occurred at concentrations close to those observed in human plasma (0.2-0.6 PM). The results support a possible role of 27-hydroxycholesterol, a physiological oxysterol, in the regulation of cellular cholesterol homeostasis in non-hepatic tissues.
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