The regulatory role of very low density lipoproteins (VLDL) in de novo protein synthesis and in natural killer (NK) mediated cytotoxicity against cancer cells was evaluated in IL-2 activated peripheral blood mononuclear cells (PBL). Supplementing of VLDL to the incubation medium induced a potent dose-related inhibitory effect on the synthesis and secretion of (35S) labelled proteins. The maximal inhibitory response was observed at 50 micrograms/ml cholesterol VLDL. The effect of VLDL on the IL-2 induced ability of lymphocytes to kill cancer cells and to interfere with target cell proliferation was then evaluated. Maximal cytotoxicity was observed at 50 micrograms VLDL/ml as cholesterol. This VLDL-dependent stimulatory effect was associated with a significant decrease in the proliferative effect of the medium conditioned by PBL. The possibility that VLDL mediate the regulation of immune functions by interacting with metabolic patterns expressed by IL-2 stimulated lymphocytes is discussed in light of these results.

Adult↗

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Effect of the nifedipine-atenolol association on arterial myocyte migration and proliferation.

The in vitro effect of nifedipine and atenolol, either alone or in combination, on the proliferation and migration of rat aortic smooth muscle cells was investigated. Nifedipine inhibited the replication of arterial myocytes in concentrations ranging between 10 and 100 microM. The inhibition, evaluated as cell number, was dose- and time-dependent with an IC50 of 39 and 34 microM after 48 and 72 h, respectively; the cell doubling time increased with drug concentrations up to 118 h versus 28 h for controls. Atenolol alone failed to reduce arterial myocyte proliferation, and did not influence the effect of nifedipine on cell proliferation. Nifedipine and atenolol alone inhibited in a dose-dependent manner rat aortic myocytes migration induced by fibrinogen as chemotactic agent. When the combination nifedipine-atenolol was investigated, an additive inhibitory effect on cell migration was observed. These results provide in vitro support for a potential effect of this drug association on early steps of atherogenesis.

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Effects of coffee on plasma lipids, lipoproteins and apolipoproteins.

The acute effects of coffee, cigarette smoking and alcohol on serum lipids, lipoproteins and thromboxane B2 production by platelets were studied in nine healthy volunteers who were non-drinkers of coffee and alcohol and non-smokers. They received, in a single administration, coffee (containing 200 mg of caffeine), alcohol (0.50 ml/kg body wt), or smoked two cigarettes. No differences were observed between baseline and 15, 60 and 80 min values for plasma cholesterol, triglycerides, HDL cholesterol, plasma apolipoproteins A-I and B and thromboxane B2 production. Chronic coffee consumption also did not affect either plasma lipoprotein profile or the interaction of low density lipoproteins with cellular receptors in a group of healthy individuals. These results suggest that coffee itself does not affect acutely the plasma lipoprotein profile in healthy man. This was also true in heavy coffee drinkers.

Adult↗

PubMedDate not supplied

Trapidil derivatives and low density lipoprotein metabolism by human skin fibroblasts and by human hepatoma cell line Hep G2.

The effect of trapidil (RocornalR) and some of its newly developed derivatives (AR 12456, AR 12463, AR 12465, AR 12464) on the receptor-mediated low density lipoprotein (LDL) binding, uptake and degradation was studied in human skin fibroblasts (HSF) and in human hepatoma cell line Hep G2. Compound AR 12456 influenced this pathway in a selective way: it enhanced the uptake and degradation of 125I-LDL by Hep G2 cells in a dose-dependent manner, but inhibited it in HSF. Scatchard analysis of the saturable LDL binding in Hep G2 indicates that the effect of compound AR 12456 is the result of an increased number of LDL binding sites. Compound AR 12465 was less effective on LDL catabolism. Trapidil and the other derivatives were inactive under the same experimental conditions. When Ar 12456 was preincubated with Hep G2 cells and then the incubation medium was transferred to HSF, a stimulation of specific LDL pathway occurred also in this cell line. These findings suggest that a metabolite(s) of AR 12456 might be responsible for the enhanced expression of LDL receptors in cultured human cells.

Animals↗

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In vitro inhibition of arterial myocyte growth and stimulation of low density lipoprotein metabolism by SIM 6080, a new calcium antagonist.

We have investigated the in vitro effect of the new calcium antagonist SIM 6080 on proliferation of rat aortic smooth muscle cells and on LDL receptor-mediated catabolism in human fibroblasts. Verapamil was used as the reference compound. SIM 6080 inhibited the proliferation of rat aortic myocytes in concentrations ranging between 1 and 20 microM. The inhibition, evaluated as cell number and nuclear incorporation of [3H]thymidine, was dose and time dependent; the cell doubling time increased with drug concentrations up to 69 h versus 20 h for controls. Similar results on both LDL pathway and smooth muscle cell proliferation were achieved with verapamil, but higher concentrations were needed. The specific uptake and degradation of 125I-LDL was evaluated in human fibroblasts after 48 h incubation with SIM 6080 (1-10 microM). The compound dose dependently enhanced the receptor-mediated 125I-LDL uptake, with a fourfold increase as a maximal effect (10 microM); LDL degradation was less sensitive to the drug. The present results provide evidence that the new calcium antagonist SIM 6080 interferes in vitro with processes involved in atherogenesis.

Animals↗

PubMedDate not supplied

Established facts, doubts and future perspectives on PGI2 vascular and platelet receptors.

Explore the source record for details and available documents.

Animals↗

PubMedDate not supplied

Lipid-modified proteins as biomarkers for cardiovascular disease: a review.

Lipid-modified proteins are classified based on the identity of the attached lipid, a post- or co-translational modification required for their biological function. At least five different lipid modifications of cysteines, glycines and other residues on the COOH- and NH(2)-terminal domains have been described. Cysteine residues may be modified by the addition of a 16-carbon saturated fatty acyl group by a labile thioester bond (palmitoylation) or by prenylation processes that catalyze the formation of thioether bond with mevalonate derived isoprenoids, farnesol and geranylgeraniol. The NH(2)-terminal glycine residues may undergo a quite distinct process involving the formation of an amide bond with a 14-carbon saturated acyl group (myristoylation), while glycine residues in the COOH-terminal may be covalently attached with a cholesterol moiety by an ester bond. Finally, cell surface proteins can be anchored to the membrane through the addition of glycosylphosphatidylinositol moiety. Several lines of evidence suggest that lipid-modified proteins are directly involved in different steps of the development of lesions of atherosclerosis, from leukocyte recruitment to plaque rupture, and their expression or lipid modification are likely altered during atherogenesis. This review will briefly summarize the different enzymatic pathways of lipid modification and propose a series of lipid-modified proteins that can be used as biomarkers for cardiovascular disease.

Acyltransferases↗

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Non-lipid-related effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

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 lipids, HMG-CoA reductase inhibitors exert a direct antiatherosclerotic effect on the arterial wall, probably through local inhibition of isoprenoid biosynthesis.

Animals↗

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The expression of proto-oncogene c-jun in human pancreatic cancer.

The proto-oncogene c-jun is involved in cellular proliferation by interfering with signals that lead to cellular differentiation. Moreover the induction of metalloproteinase gene appears to utilise the c-jun oncogene as intracellular messenger. The aims of this study were to evaluate a) the expression of c-jun oncogene in pancreatic cancer b) its relation with tumor histological features. Surgical specimens of pancreatic cancer were collected from 22 patients radically operated upon, and from 11 submitted to palliation. As a control group, 5 specimens of normal pancreas and 5 specimens of chronic pancreatitis were studied. C-jun staining was graded as follows: (-) positive cells < 10%, (+) from 10 to 30%, (+2), from 30 to 60%, (+3) from 60 to 90%. Glucagon and somatostatin staining was graded counting the positive cells of total numer of Langherans islet cells counted. c-Jun expression (low: < 30% and high: > 30%) was related to stage, architectural and cytological grading, vascular, lymph nodal, perineural invasion. Normal pancreas and chronic pancreatitis tissues appear to express the c-jun protein in less than 10% of ductal cells. The percentage of tumor cells stained for c-jun is increased as compared to the control group in 28/33 cases: in 13 (46%) it ranges from 10 to 30%; in 10 (36%) from 30 to 60% and in 5 (18%) from 60 to 90%. The frequency of high or low c-jun expression is not different in relation to the histological features of tumor. Moreover, c-jun protein is present in 40% of cells of Langherans islets in normal pancreas, chronic pancreatitis and pancreatic cancer. The Langherans islet cells stained for c-jun exhibit also a positivity for glucagon. In conclusion; a) in pancreatic cancer, the expression of c-jun is increased in tumour cells in majority of cases as compared to the control group, b) a c-jun positivity is also found in alpha cells with a pattern not different from control group, but the relation between the alpha cells and c-jun production is unknown, c) c-jun expression does not vary in relation to histological findings.

Adult↗

PubMedDate not supplied

Laparostomy in the treatment of severe peritonitis: a review of 60 cases.

The aim of this study was to evaluate the use of laparostomy in the management of patients with severe abdominal infections. From June 1992 to December 2000 sixty patients with severe peritonitis were treated with laparostomy and studied retrospectively. Thirty-eight had post-operative peritonitis. Twelve patients had necrotic pancreatitis. Five patients had peritonitis due to ischemic colitis. Two patients had hemoperitoneum following multiple abdominal operations, and three patientshad severe wound dehiscence. The APACHE II score was used to determine the severity of patients' condition. The median age was 46 years, the mean APACHE II score was 19.7, and the observed mortality was 38.3%. The incidence of spontaneous fistulation of the exposed loop of intestine was 13.3%. In 11 patients abdominal wall closure was accomplished by primary intention. Incisional hernias were inevitable in the rest of patient and were repaired 1 years after surgery. Laparostomy is a good way to manage patients with severe peritonitis but it should be performed before irreversible septic shock and subsequent multi organ failure develop.

Adult↗