A comparative study on dyslipidaemia inducing diets in various rat strains.

In our experiments we compared the serum lipoprotein lipid composition of Fischer 344 (F344) and Long-Evans (LE) inbred rats as well as of their hybrid FLF(1) from both sexes after feeding them for 2, 4 and 8 weeks with different diets. The following diets were used: 1) standard diet marked as CRLT/N; 2) diet reach in butter marked as BR; 3) diet containing cholesterol, sodium cholate and methylthiouracil marked as CR; 4) diet marked as BRC, which is the Hartroft-Sós diet modified by our research group consisting of the diets BR and CR. The latter diet was the most effective, because within two weeks the level of serum total cholesterol, LDL-cholesterol, HDL-cholesterol and triglyceride in the F344 female rats increased 8, 30, 4 and 8 times, respectively.

Obesity abrogates the concentration-dependent effect of leptin on endogenous cholesterol synthesis in human monocytes.

Leptin the cytokine-like hormone is involved not only in local inflammations, but it regulates cholesterol biosynthesis in human monocytes. Since, monocyte-membrane composition in obesity shows considerable difference from control cells, our aim was to elucidate the concentration dependence of the effect of leptin in OW monocytes, and the downstream signaling of high and low leptin concentrations. Control and OW monocytes were stimulated with leptin in the presence or absence of different inhibitors.

The concentration dependent biphasic effect of leptin on endogenous cholesterol synthesis in human monocytes.

In human monocytes 100 ng/mL leptin increased both statin-inhibitable free radical and cholesterol production in vitro. In our recent study, we aimed to elucidate the concentration dependence of observed leptin-effect. Following leptin stimulation cholesterol synthesis was measured in the presence of inhibitors to determine affected signal pathways.

Leptin stimulates endogenous cholesterol synthesis in human monocytes: New role of an old player in atherosclerotic plaque formation. Leptin-induced increase in cholesterol synthesis.

The role of leptin in the pathomechanism of atherosclerosis, through its free radical generating ability is established. Its effect however, on the regulation of intracellular cholesterol synthesis has not been studied. The aim of the present study was to elucidate whether leptin influences endogenous cholesterol synthesis in monocytes.

The association between angiotensin II-induced free radical generation and membrane fluidity in neutrophils of patients with metabolic syndrome.

Angiotensin II (Ang II) is able to induce free radical generation in neutrophils, which is more elevated in neutrophils of patients with hypercholesterolemia (HC). In addition, the signal processing through angiotensin I (Ang I) receptors is altered. In present study, we compared the Ang II-triggered free radical generation of neutrophils obtained from patients with relatively isolated forms of metabolic syndrome (MS) with membrane-bound cholesterol content and membrane fluidity.

Neuropeptides induced a pronounced and statin-sensitive dysregulation of mevalonate cycle in human monocytes of patients with hypercholesterolemia.

Angiotensin II (Ang II) and leptin generate statin-inhibitable superoxide anion production that accounts for only part of the entire superoxide anion production. In our recent studies, we aimed at elucidating whether Ang II and leptin, affecting the intensity of the mevalonate cycle, are able to increase endogenous cholesterol synthesis. Furthermore, we compared the superoxide anion and cholesterol production capability of monocytes of healthy control volunteers and monocytes obtained from patients with hypercholesterolemia (HC).

Crosstalk of sterol-dependent and non-sterol-dependent signaling in human monocytes after in vitro addition of LDL.

The aim of the present study was to investigate low density lipoprotein (LDL)-induced, non-sterol-dependent signaling and its possible role in cholesterol balance. LDL in 10 microg ml(-1) concentration could induce inositol trisphosphate (IP3) and Ca2+ signal generation through a pertussis toxin (PT) sensitive G protein in human monocytes. The increase in [Ca2+]i was derived from the intracellular pools.

Angiotensin II-induced oxidative burst is fluvastatin sensitive in neutrophils of patients with hypercholesterolemia.

The aim of this study was to investigate the effect of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor fluvastatin (Flu) on angiotensin II (AII)-stimulated neutrophils of patients with hypercholesterolemia. Results suggest that a 6-week-long Flu administration completely counteracted the AII-induced increase in superoxide anion and leukotriene C4 production of the neutrophils of patients with hypercholesterolemia. However, the failure of signal processing through pertussis toxin-sensitive G protein, the increase in [Ca2+]i in membrane-bound protein kinase C activity, and the increase in neutrophil-bound cholesterol content were only partially restored by Flu.

Different anticancer effects of fluvastatin on primary hepatocellular tumors and metastases in rats.

Rats (FLF1) were pretreated with 2 and 20 mg/kg/day fluvastatin (Flu), and after 6 weeks, hepatocellular tumor cells were inoculated under the left renal capsule. At different times, growth and pyruvate kinase (PK) activity of the primary tumors and lymph node metastases were determined. Flu had a dose-dependent inhibitory effect on primary and metastatic tumors, and the inhibitory effect on growth and PK activity in metastases were higher than in primary tumors.

HMG CoA reductase inhibitor fluvastatin arrests the development of implanted hepatocarcinoma in rats.

Background: Fluvastain (Flu) is widely accepted to have anticancer effect although its in vivo chemopreventive ability in cancer has not been studied. The therapeutic and chemopreventive effects of Flu were compared in vivo in the present study.

Materials And Methods: Under the left renal capsule of FLF1 hybrid rats 10(6) hepatocarcinoma cells were implanted (He/De14) on sponge disc.

Disturbed regulation of cholesterol synthesis in monocytes of obese patients with hypercholesterolemia.

The aim of the present study was to clarify the influence of obesity on the functions of low-density lipoprotein receptors (LDL-R) and 3-hydroxy-3-methylglutarate-coenyzme A (HMG-CoA) reductase both in healthy control subjects and in patients with hypercholesterolemia (HC). Experiments were performed on monocytes of 15 non-obese (C I) and 11 obese (C II) healthy control subjects and on 22 non-obese (HC I) and 26 obese (HC II) patients with HC. [(125)I]LDL was used to determine LDL-R activity by measuring binding and intracellular degradation.

Altered signal pathway in angiotensin II-stimulated neutrophils of patients with hypercholesterolaemia.

Angiotensin II (AII) in 1-10 nM concentrations has an in vivo immunostimulating effect on human neutrophils. The release of superoxide anions and leukotrienes (LTs) is significantly increased by 10 nM AII-stimulated neutrophils of patients with hypercholesterolaemia (HCH). These oxidizing agents may be involved in the damage of vessel walls, i.

Disturbed LDL and scavenger receptor functions in monocytes from chronic haemodialysed patients.

Background: The most frequent complication in patients with end-stage renal failure on chronic haemodialysis (HD) treatment is atherosclerosis, i.e. the different forms of heart and vascular diseases.

Altered signal pathway in granulocytes from patients with hypercholesterolemia.

In the present study the signal transduction of the formyl-Met-Leu-Phe receptor was studied in granulocytes obtained from control subjects and patients with elevated low density lipoprotein levels. According to our results, 10 nm formyl-Met-Leu-Phe in control cells activates phospholipase C inducing a pronounced inositol phosphate production followed by a Ca(2+) signal from intracellular pools. The pertussis toxin-sensitive O(2)(-) generation and leukotriene synthesis were moderate.

Heterogeneous signal pathways through TSH receptors in porcine thyroid cells following stimulation with Graves' immunoglobulin G.

Objective: We compared different signal transduction pathways through thyroid stimulating hormone receptor (TSH-R) in porcine thyroid cells (PTC) following stimulation with thyroid stimulating hormone (TSH) and 11 thyroid stimulating immunoglobulin samples (TSI) obtained from patients with Graves' disease.

Design: Following stimulation with TSI, the level of inositol trisphosphate (IP3) and [Ca2+]i, as well as the membrane bound protein kinase C (PKC) activity and the intensity of the arachidonic acid (AA) cascade, were determined in PTC.

Results: Seven out of eleven TSI samples activated PTC through IP3 generation, elevated [Ca2+]i from the intracellular pools, exhibited verapamil-insensitive membrane-bound PKC activation, and enhanced release of [14C]AA derivates (however, one of the samples was also able to take up Ca2+ from the extracellular space).

Specific and scavenger low-density lipoprotein receptors involved in the disturbed lipid metabolism of patients with non-insulin-dependent diabetes mellitus are independent of obesity.

Comparative studies were performed on monocyte-derived macrophages (MDMs), prepared by a 72-hour incubation of blood monocytes obtained from patients with non-insulin-dependent diabetes mellitus (NIDDM) and age-matched obese and non-obese controls. The MDMs, after a 72-hour culturing, expressed both specific and scavenger low-density lipoprotein (LDL) receptors on their surfaces. To study the binding capacity of both receptor types, [125I]LDL and [125I] acetylated LDL (acLDL) were applied to cells and the labeled ligands were then monitored to estimate the rate of intracellular degradations.

Altered postreceptor signal transduction of formyl-Met-Leu-Phe receptors in polymorphonuclear leukocytes of patients with non-insulin-dependent diabetes mellitus.

The signal transduction of the formyl-Met-Leu-Phe (FMLP) receptor in polymorphonuclear leukocytes (PMNLs) from patients with non-insulin-dependent diabetes mellitus (NIDDM) was compared to that of PMNLs obtained from healthy volunteers. According to our previous studies in this group of patients neither the decrease in insulin binding capacity nor the enhanced insulin-degrading enzyme activity was involved. In control PMNLs, 10 nM FMLP induced a pertussis toxin-sensitive increase in phosphatidyl inositol (PI) cleavage and a subsequent Ca2+ signaling from the intracellular pools.

[Intracellular signal transmission of low density lipoprotein receptors in human monocytes].

The authors found that in human monocytes administered low density lipoprotein in doses of 50 micrograms had optimal inhibition of endogenous cholesterol synthesis which measured by [14C] acetate incorporation. There was not effect of pertussis toxin and phorbol myristate acetate on the inhibiton of endogenous cholesterol synthesis, whereas calcium channel blocker verapamil and phospholipase A2-inhibitor chloroquine decreased it. In contrast, the protein kinase C-stimulant phorbol myristate acetate alone had effects as LDL, but the protein kinase C-inhibitor H-7 had antagonist effect against LDL.

[Abnormal function of lipoprotein receptors in the monocytes of hypercholesteremic patients].

The familial hypercholesterinemia (HCh) is as a genetically determined disorder. The genetical damage and functional abnormalities of the LDL receptors lead to familial Hch. The LDL plays an important role in cholesterol metabolism.

[Biologic effect of LDL binding and intracellular degradation in monocytes from patients with hypercholesterolemia].

The granulocytes from elderly patients were investigated, in previous studies, with FMLP and it was found that the postreceptor signal, the inositol phosphate production and inositol phosphate dependent calcium signal were markedly reduced. It was observed that the 125I LDL binding was slightly reduced while the intracellular degradation of the LDL and endogenous cholesterol synthesis inhibitory effect was significantly decreased on monocytes of patients with non insulin dependent diabetes mellitus. It was suggested that of in patients suffering from NIDDM with hypercholesterolemia the LDL receptor numbers of monocytes are close to normal, while the post receptor signal transmission is damaged.

Parameters of respiratory burst and arachidonic acid metabolism in polymorphonuclear granulocytes from patients with various thyroid diseases.

The oxidative processes (oxygen consumption, superoxoid anion generation, arachidonic acid cascade) of human polymorphonuclear granulocytes (PMNs) obtained from patients suffering from thyroid disorders of autoimmune origin (Graves' disease and Hashimoto's thyroiditis), and non autoimmune origin (toxic adenoma) were investigated. All Graves' and toxic adenoma patients were hyperthyroid. Hashimoto's thyroiditis patients were euthyroid.

Disturbed intracellular calcium-related processes of hepatocytes and neutrophils in human alcoholic liver disease.

Isolated human hepatocytes and separated neutrophils of 11 patients with alcoholic liver disease (ALD) were used to study some aspects of cellular calcium-related processes compared to nonalcoholic controls. 45Ca2+ efflux from the cells decreased in ALD and the calmodulin-inhibitor trifluoperazine did not influence it further. The intracellular free calcium concentration [( Ca2+]i) of nonstimulated hepatocytes and neutrophils proved to be higher in ALD with the Quin2/AM loading technique.

Altered post-receptorial signal transduction mechanism under various stimulation in polymorphonuclear granulocytes of Alzheimer's disease.

The cyclic nucleotide changes were studied under 10(-6) M isoproterenol (IP), 10(-6) M carbachol and 10(-8) M Met-enkephalin (Met-enk) stimulations in polymorphonuclear granulocytes (PMNLs) of middle-aged (aged 35-52 years) and elderly (aged 61-97 years) healthy subjects, as well as of patients with Alzheimer's disease (AD) (aged 58-65 years). From our results we can conclude that in the case of middle-aged healthy subjects only the IP caused a marked cAMP elevation while in elderly and AD all the applied substances stimulated the cAMP at different degrees. Concerning the cGMP levels in PMNLs, we observed a marked increase under carbachol and Met-enk stimulation, in middle-aged subjects, while in the elderly a weak change was obtained by carbachol.

Age related impairment in phosphatidylinositol breakdown of polymorphonuclear granulocytes.

It is well known that with aging the immune response decreases. Most of the effector functions occur through specific receptors. Thus, we investigated the effects of various stimulants, acting through receptors or directly through the GTP-binding Gi protein, on phosphatidylinositol breakdown in PMNLs of young and elderly subjects and try to modulate it.