Aspirin and PPAR-alpha activators inhibit monocyte chemoattractant protein-1 expression induced by high glucose concentration in human endothelial cells

Activated endothelial cells express monocyte chemoattractant protein-1 (MCP-1), a chemokine which is reportedly involved in the recruitment of plasma monocytes in the early stages of atherosclerosis. Since accelerated atherosclerosis is the main complication of diabetes and both diseases encompass an inflammatory reaction, we hypothesized that the anti-inflammatory drugs, aspirin and peroxisome proliferator-activated receptor (PPAR-alpha) activators (fenofibrate and clofibrate), could have an effect on the high glucose-induced MCP-1 expression in endothelial cells. To test this assumption, as well as the possible mechanisms involved, the MCP-1 expression and secretion, the reactive oxygen species levels, nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) expression were determined in human endothelial cells exposed to high glucose concentrations in the presence of aspirin, fenofibrate and clofibrate. Human endothelial cells kept in normal glucose concentration in the absence of drugs were used as control. The results showed that (i) aspirin, fenofibrate and clofibrate decrease significantly the MCP-1 expression and secretion in human endothelial cells; (ii) the high glucose up-regulated expression of MCP-1 in endothelial cells was significantly reduced by inhibitors of NF-kB and reactive oxygen species; (iii) all drugs notably decrease the level of the reactive oxygen species and activation of NF-kB and AP-1. Together, the findings indicate that in endothelial cells aspirin and PPAR-alpha activators reduce the high glucose-increased expression of MCP-1 by a mechanism that includes the inhibition of reactive oxygen species, and decrease of AP-1 and NF-kB activation.     

History repeats itself: pharmacodynamic trends in the treatment of anxiety disorders

The original treatment indicated for those suffering from neurotic anxiety was to employ psychotherapy to facilitate changes in behavior and coping with stressful events. A spectrum of somatic treatments "from cathartics and emetics to opium and "strengthening tonics", from atropine and digitalis to potassium bromide and chloral hydrate, from barbiturates to benzodiazepines", to serotonergics, came to be used as well [1]. The Food and Drug Administration originally approved many gamma-aminobutyric acid (GABA) facilitating drugs since the 1960s for anxiety treatment. The 1980s evidenced the approval of a few serotonergic treatments that cornered the prescribing market and the front line of most treatment protocols. More recently, GABAergic drugs are making a return in the treatment of anxiety disorders. The following paper details the pharmacodynamic history of treating anxiety and also updates the reader as to the newer GABA-based approaches mentioned above.     

Neovascular glaucoma--retrospective study

The paper realized the retrospective evaluation of all cases of neovascular glaucoma hospitalized in Clinic of Ophthalmology of Craiova in the last 15 years. Neovascular secondary glaucoma represents 3,9% of all glaucomas. The most important etiologic factors were the central venous occlusion, diabetic retinopathy, carotid occlusion, intraocular tumors, chronic uveitis, Fuchs heterochromy. Neovascular secondary glaucoma is characterized by important hypoxic tissues destructions, presented of all levels that lead to neovessels formation with irreversible anatomic and functional losing of ocular globe. The identification of neovascular glaucoma causes and their treatment is important to prevent that diseases.     

Enoxaparin--a low molecular weight heparin,restores the altered vascular reactivity of resistance arteries in aged and aged-diabetic hamsters

We questioned whether the low molecular weight heparin enoxaparin acts upon the altered vascular reactivity of the resistance arteries in normal biological aging and in aging associated with diabetes. Experiments were performed on isolated resistance arteries of young (4 months old), aged (16 months old), and aged-diabetic hamsters (16 months old and 5 months since streptozotocin injection), and the reactivity was assessed by the myograph technique. The results showed that enoxaparin (60 microg/ml) had favorable effects on the vascular reactivity in aged and aged-diabetic conditions, i.e., diminished the contractility of the arterial wall to 10(-8)-10(-6) M noradrenaline (NA) and to K(+), and potentiated the impeded endothelium-dependent relaxation to 10(-8)-10(-4) M acetylcholine (ACh). The effect was more pronounced compared to that produced by unfractionated heparin (UFH). These pharmacological effects supplement the anticoagulant properties of enoxaparin and may be of relevance for improving perfusion/circulation in the microvasculature of aged and of aged-diabetic persons.     

Partial chemical characterization of the anionic sites in the basal lamina of fenestrated capillaries

The distribution of anionic sites in the basal laminae of the blood capillaries of the murine pancreas was studied in specimens fixed in ruthenium red (RR)-glutaraldehyde mixtures. The sites appeared as discrete, small (6 to 18 nm) particles distributed throughout the three laminae but concentrated primarily in the lamina rara externa, in which—spaced 80–100 nm apart—they formed a planar, partially ordered lattice comparable to that revealed by cationized ferritin in previous studies (M. Simionescu, N. Simionescu, and G. E. Palade, 1982, J. Cell Biol.95, 425–434). The chemical nature of the anionic sites was explored by incubating fresh tissue specimens in solutions of selected enzymes before fixation in RR-glutaraldehyde mixtures. Pronase P and papain removed completely the anionic sites and left behind an extensively degraded and disorganized basal lamina. Trypsin caused the removal of anionic sites only, did not degrade the rest of the basal lamina, but detached it completely from the endothelium. Chondroitinase ABC reduced slightly the size and the surface density of RR-stainable particles, and detached focally the rest of the basal lamina from the endothelium and pericytes. Crude heparinase caused a nearly complete removal of anionic sites, and pure heparitinase gave comparable but less extensive results. Similar effects were recorded on the basal laminae of smooth muscle fibers and pancreatic acini and ducts. The results indicate that the anionic sites of all basal laminae examined are contributed primarily by heparan sulfate proteoglycans and trace amounts of chondroitin sulfate proteolycans.     

Effects of cobalt-60 gamma-irradiation in association with prostaglandin E1 treatment on the cyclic AMP levels of some radiosensitive tissues.

The amounts of cyclic AMP in brain, liver and intestinal mucosa have been measured in rats, at constant intervals, up to 18 days after whole-body exposure to either a unique moderate dose (500 rd) or a unique lethal dose (750 rd) of cobalt-60 gamma-radiation in association with a preliminary intraperitoneally treatment with prostaglandin E1 (5 microgram/100 g body weight/day) during five days. The amounts of tissular cyclic AMP in these two experimental groups were compared with those obtained from control groups identically irradiated or treated with prostaglandin E1. The effects of gamma-irradiation and prostaglandin E1 treatment on the cyclic AMP levels were found to be quite specific in these organs, suggesting that they contain different adenyl cyclase-cyclic AMP-phosphodiesterase systems: a cerebral system which is influenced by both gamma-radiation and prostaglandin E1, a hepatic system which is "radioresistant" and an intestinal system which is not influenced by prostaglandin E1. When associated with gamma-radiation, this prostaglandin is capable, on the one hand, to annul the "radioresistance" of the hepatic cyclic AMP system and, on the other hand, to annul the "radiosensitivity" of the intestinal cyclic AMP system.     

Experimental obstructive coronary atherosclerosis in the hyperlipidemic hamster

The evolution of coronary atherosclerotic lesions induced by a hyperlipidemic diet was examined in male hamsters subjected for up to 40 weeks to a standard chow supplemented with 3% cholesterol and 15% butter. Control animals were fed standard chow only. Five to seven hamsters were monthly sacrificed and investigated for serum lipids and coronary artery lesions. As compared with control animals, the hamsters fed the fat diet showed a progressive increase in serum cholesterol which reached maximum values up to 17 fold in the 10th month. The serum of the hyperlipidemic hamster examined by agarose electrophoresis, Laurell immunoelectrophoresis and cross-immunoelectrophoresis showed at most a 14 fold increase in low density lipoproteins after 10 months diet. The examination of coronary arteries revealed morphologic changes already detectable at 2 weeks of diet. The earliest modifications observed were characterized by proliferation of the subendothelial matrix or/and the appearance of liposome-like structures in the intima. After 2-3 weeks of diet, smooth muscle cells appeared occasionally in the intima and monocytes adhered and penetrated through the endothelium. Later on, smooth muscle cells and macrophage displayed lipid deposits. Focally, in areas of intimal proliferation and foam cells, endothelial cells were also lipid-loaded. Like in human atherosclerotic plaque, in the late stages of hamster coronary lesions, there was a progressive accumulation of extracellular unesterified cholesterol, calcium deposition and necrosis. Lesions evolved to a progressive narrowing of the coronary branches affected, with complete obstruction of some small arterial ramifications. Hamster appears to be a suitable model for studying the molecular and cellular events leading to obstructive coronary atherosclerosis.     

Endothelial cell-derived foam cells fail to express adhesion molecules (ICAM-1 and VCAM-1) for monocytes

The purpose of this study was to assess the expression of cell adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and VCAM-1 (vascular cell adhesion molecule-1) in endothelial cell-derived foam cells. Hamster aortic endothelial cells (HAEC) in culture were exposed to hypercholesterolemic or normal homologous serum for 24 h. At the end of the incubation period, HAEC exposed to hypercholesterolemic serum exhibited numerous lipid droplets and had a general aspect of foam cells. When examined for the expression of ICAM-1 and VCAM-1 (by indirect immunofluorescence) normal HAEC expressed constitutively (to low level) on their surface these adhesion molecules; however HAEC-derived foam cells failed to display any labeling. To further assess these results, HAEC were first incubated with normal or hypercholesterolemic sera (as above) and then exposed to freshly isolated normal hamster blood monocytes. These experiments showed that monocytes adhered in small number to normal cells and failed to adhere to the surface of HAEC-derived foam cells. Together these data indicate that endothelial cell-derived foam cells: a) do not express ICAM-1 and VCAM-1 on their surface; b) have low or no adhesion properties for monocytes and c) may represent an appropriate experimental model to study the cellular alterations that take place in the advanced stages of atherosclerosis.     

Plant-Based versus Animal-Based Low Protein Diets in the Management of Chronic Kidney Disease

Recent data reiterate low-protein diets (LPDs) as cornerstones in the conservative management of chronic kidney disease (CKD). The reduction in proteinuria, better blood pressure control and the reduction in the rate of decline in kidney function with LPDs were reported, both in non-diabetics and diabetics patients. Supplemented, vegetarian, very-low-protein diets (sVLPD, 0.3 g/kg-day) could postpone kidney replacement therapy (KRT) initiation, mainly through the better control of metabolic disorders of advanced CKD in non-diabetic patients. Plant-based diets could ameliorate gut microbiota and appear to be superior to mixed hypoproteic diets in treating advanced CKD: better control of nitrogen balance, acid-base metabolism and bone mineral disorders. Vegetarian diets generate fewer uremic toxins and reduce salt intake and acid overload. At the same time, they can improve lipid metabolism, providing a high ratio of unsaturated to saturated fatty acids, as well as insulin resistance.