氧化型和正常极低密度脂蛋白对猪主动脉平滑肌细胞脂类堆积的不同影响

为了观察氧化型及正常极低密度脂蛋白对血管平滑肌细胞内脂类堆积的不同影响，探索平滑肌细胞摄取氧化型极低密度脂蛋白的受体途径，用２００ｍｇ／Ｌ的氧化型及正常极低密度脂蛋白与猪主动脉平滑肌细胞温有４８ｈ后，细胞内甘油三脂含量分别为对照组的３．２倍和１０．６倍（Ｐ〈０．０１），且两个实验组之间相比，差异也有显著性意义（Ｐ〈０．０１），细胞内总胆固醇明显升高（Ｐ〈０．０５），但是两个实验组之间无显著差异（Ｐ     

Lipid lowering effect of S-methyl cysteine sulfoxide from Allium cepa Linn in high cholesterol diet fed rats

The lipid lowering action of S-methyl cysteine sulfoxide (SMCS) isolated from Allium cepa Linn (family: Liliaceae) was investigated in Sprague-Dawley rats fed on 1% cholesterol diet, in comparison to the hypolipidemic drug gugulipid. Administration of SMCS at a dose of 200mg/kg body weight for 45 days ameliorated the hyperlipidemic condition. The lipid profile in serum and tissues showed that concentrations of cholesterol, triglyceride and phospholipids were significantly reduced when compared to their untreated counterparts. The total lipoprotein lipase activity in the adipose tissue was decreased with also a decrease in the free fatty acid levels in serum and tissues. The activities of the lipogenic enzymes glucose 6-phosphate dehydrogenase and malic enzyme as also of HMG CoA reductase in the tissues remained low on treatment indicating that both the drugs did not favor lipogenesis and cholesterogenesis in the hyperlipidemic animals. The fecal excretion of bile acids and sterols was further increased upon treatment with the drugs. The results are directive to that both gugulipid and SMCS cause reduction of endogenous lipogenesis, increase catabolism of lipids and subsequent excretion of metabolic by-products through the intestinal tract. However, gugulipid is a better drug than SMCS at a low dose of 50mg/kg body weight.     

The hypolipidaemic activity of aqueous Erica multiflora flowers extract in Triton WR-1339 induced hyperlipidaemic rats: a comparison with fenofibrate

In the present study, an aqueous extract from Erica multiflora L. (Ericaceae) flowers was evaluated for its hypocholesterolaemic and hypotriglyceridaemic activities using Triton WR-1339 induced hyperlipemic rats as experimental model. Hyperlipideamia was developed by intraperitonial injection of Triton (200mg/kg body weight). The animals were divided into control (CG), hyperlipidaemic (HG), hyperlipidaemic plus herb extract (HG+EmE) and hyperlipidaemic plus fenofibrate (HG+FF) treated groups. Intragastric administration of Erica multiflora extract (0.25 g/100g body weight) to the rats caused a significant decrease on their plasma lipid levels (quantified using enzymatic kits). At 7h after treatment, plasma total cholesterol, triglycerides and LDL-cholesterol were decreased by 47%, 95% and 67%, respectively, but the change of HDL-cholesterol level was not significant. However, the hypolipidaemic effect of fenofibrate was limited to triglycerides and LDL-cholesterol, which were lowered by about 92% and 41%, respectively. At 24h after treatment, Erica multiflora extract reduced plasma total cholesterol by 68.5% and triglycerides by 91%. HDL-cholesterol was not significantly increased and LDL-cholesterol was lowered by 80.5%. In fenofibrate treated rats, only plasma triglyceride concentrations were lowered by 82%, while the other lipid parameters were not significantly changed indicating that this aqueous herb extract may contain products that lower plasma lipid concentrations and might be beneficial in treatment of hyperlipideamia.     

Oxysterols: A world to explore

Oxysterols (oxidized derivatives of cholesterol and phytosterols) can be generated in the human organism through different oxidation processes, some requiring enzymes. Furthermore, oxysterols are also present in food due to lipid oxidation reactions caused by heating treatments, contact with oxygen, exposure to sunlight, etc., and they could be absorbed from the diet, at different rates depending on their side chain length. In the organism, oxysterols can follow different routes: secreted into the intestinal lumen, esterified and distributed by lipoproteins to different tissues or degraded, mainly in the liver. Cholesterol oxidation products (COPs) have shown cytotoxicity, apoptotic and pro-inflammatory effects and they have also been linked with chronic diseases including atherosclerotic and neurodegenerative processess. In the case of phytosterol oxidation products (POPs), more research is needed on toxic effects. Nevertheless, current knowledge suggests they may also cause cytotoxic and pro-apoptotic effects, although at higher concentrations than COPs. Recently, new beneficial biological activities of oxysterols are being investigated. Whereas COPs are associated with cholesterol homeostasis mediated by different mechanisms, the implication of POPs is not clear yet. Available literature on sources of oxysterols in the organism, metabolism, toxicity and potential beneficial effects of these compounds are reviewed in this paper.     

Differences in circadian variations of tissue factor pathway inhibitor type 1 between able-bodied and spinal cord injured

INTRODUCTION: Tissue factor pathway inhibitor type 1 (TFPI) is the physiological inhibitor of the tissue factor pathway of coagulation. TFPI is produced by endothelial cells, and most intravascular TFPI is composed of full-length TFPI associated with the endothelium. Circulating TFPI is mainly truncated and lipoprotein-associated, but a small fraction circulates in a free full-length form. Although hormonal state influences the plasma variation of TFPI between individuals, other factors like temporal variation may be important. Hence, in the current study we aimed at exploring the intra-individual variation with focus on the possible circadian variations of TFPI. MATERIALS AND METHODS: TFPI free and total antigen from 8 able-bodied and 6 tetraplegic men were measured at 12 time points during a 24 h period. RESULTS: TFPI free antigen in the able-bodied exhibited circadian variation with the highest levels (approximately 20% above mean) from 12:00 to 18:00 h and the lowest levels (approximately 15% below mean) at 09:00 and 02:00 h. In contrast, TFPI free antigen in the tetraplegic group showed no circadian variation. TFPI total antigen exhibited circadian variation in neither group, but mean TFPI total antigen was lower in the tetraplegic group compared with the able-bodied (80 versus 110 ng/mL, respectively). Notably, even if TFPI total antigen in both groups did not vary according to any specific circadian rhythm, the intra-individual variation was higher than the assay variation. CONCLUSION: TFPI free antigen exhibited circadian variations in able-bodied, but not in tetraplegic subjects and the able-bodied had higher levels of TFPI total antigen than the tetraplegic group.     

Extracellular matrix molecules and synaptic plasticity: immunomapping of intracellular and secreted Reelin in the adult rat brain

Reelin, a large extracellular matrix glycoprotein, is secreted by several neuron populations in the developing and adult rodent brain. Secreted Reelin triggers a complex signaling pathway by binding lipoprotein and integrin membrane receptors in target cells. Reelin signaling regulates migration and dendritic growth in developing neurons, while it can modulate synaptic plasticity in adult neurons. To identify which adult neural circuits can be modulated by Reelin-mediated signaling, we systematically mapped the distribution of Reelin in adult rat brain using sensitive immunolabeling techniques. Results show that the distribution of intracellular and secreted Reelin is both very widespread and specific. Some interneuron and projection neuron populations in the cerebral cortex contain Reelin. Numerous striatal neurons are weakly immunoreactive for Reelin and these cells are preferentially located in striosomes. Some thalamic nuclei contain Reelin-immunoreactive cells. Double-immunolabeling for GABA and Reelin reveals that the Reelin-immunoreactive cells in the visual thalamus are the intrinsic thalamic interneurons. High local concentrations of extracellular Reelin selectively outline several dendrite spine-rich neuropils. Together with previous mRNA data, our observations suggest abundant axoplasmic transport and secretion in pathways such as the retino-collicular tract, the entorhino-hippocampal ('perforant') path, the lateral olfactory tract or the parallel fiber system of the cerebellum. A preferential secretion of Reelin in these neuropils is consistent with reports of rapid, activity-induced structural changes in adult brain circuits.     

The effect of procyanidolic oligomers on the composition of normal and hypercholesterolemic rabbit aortas

Rabbits were fed with normal (group 1 and 2) and cholesterol rich diets (group 3 and 4) concomitantly to a daily peroral administration of 50 mg/kg procyanidolic oligomers (PCO) to groups 2 and 4. After 10 weeks, the cholesterol content of the blood serum and the excised aortic intima-media were significantly higher in groups 3 and 4 than in groups 1 and 2.The DNA, hydroxyproline, uronic acid contents were similar in aortic dry weight basis in all four groups.The intima-media samples were extracted successively with 0.15 M NaCl, 0.02 M sodium phosphate pH 7.4 (NaCl extract) and with 4M guanidinium chloride, 0.05 M sodium acetate pH 5.8 prior (G1 extract) and following (G2 extract) hydrolysis of the collagen with collagenase.The cholesterol contents of G1 extracts were higher in groups 2 and 4 than in groups 1 and 3.The cholesterol content of aortic elastin increased with cholesterol feeding (group 3). With simultaneous administration of cholesterol and PCO the cholesterol content of aortic elastin in group 4 was significantly lower than in group 3.The uronic acid contents increased in G1 extracts and in the collagenase digest with PCO treatment of both normal and hypercholesterolemic rabbits. The ratio of dermatan-sulphate to chondroitinsulphate decreased with hypercholesterolemia (group 3) and with PCO (group 2 and 4). The parallelism between increased cholesterol and uronic acid contents and modified glycosaminoglycan composition in Gl extract, indicate that the interaction of cholesterol with macromolecules of the aorta can be modulated by PCO. This drug modifies the extractibility of aortic cholesterol and glycosaminoglycans and reduces the association of cholesterol to elastin.     

Inhibition of lipoprotein lipase induced cholesterol ester accumulation in human hepatoma HepG2 cells

It has been suggested previously that lipoprotein lipase may act as a ligand to enhance binding and uptake of lipoprotein particles. In the present study we have examined the capacity of bovine milk lipoprotein lipase to induce intracellular accumulation of triglyceride and cholesterol ester by VLDL (S_f 60–400) isolated from Type IV hypertriglyceridemic subject (HTg-VLDL) in HepG2 cells, independent of its lipolytic activity. We have also attempted to elucidate the cellular receptor mechanisms responsible for these effects. HTg-VLDL-mediated increases in intracellular triglyceride and cholesterol ester were dependent on the presence of an active lipase. Bovine milk lipoprotein lipase (LPL) increases triglyceride mass by 301% ± 28% (P < 0.0005) and cholesterol ester mass by 176% ± 12% (P < 0.0005). These HTg-VLDL-mediated increases in intracellular triglyceride and cholesterol ester did not occur when heat-inactivated lipase was used. Rhizopus lipase could replace LPL and cause equivalent increases in intracellular triglyceride and cholesterol ester (472% ± 61% (P < 0.005) and 202% ± 25% (P < 0.025) respectively vs. control). HTg-VLDL treated with LPL and reisolated also caused equivalent increases (274% ± 18% (P < 0.01) and 177% ± 12% (P < 0.005) for triglyceride and cholesterol ester). LDL also caused increases in intracellular cholesterol ester (189% ± 20% (P < 0.005)), although three times more LDL cholesterol had to be added to achieve the same effect. These LDL-induced increases were effectively blocked by monoclonal antibodies directed against the B,E receptor binding domains of apo B (−97% ± 13% (P < 0.0005) with anti-apo B 5E11 and − 68% ± 13% (P < 0.05) for anti-apo B B1B3) or by anti-B,E receptor antibodies (− 77% ± 7% (P < 0.01) antibody C7). These same antibodies had little effect on the HTg-VLDL + LPL-induced increases in cholesterol ester (+21%, + 15% and − 22% for 5E11, B1B3 and C7, respectively). Monoclonal anti-apo E antibodies also had no effect on LDL-mediated increases in intracellular cholesterol ester, but had a small and significant effect on VLDL-mediated increases in cholesterol ester. However, heparin, which interferes with cell surface proteoglycan interaction, was very effective at blocking HTg-VLDL-mediated increases in cholesterol ester in the presence of LPL (− 86% ± 8% P < 0.0005). Heparin was also effective in the presence of Rhizopus lipase (−79%) or lipolyzed re-isolated HTg-VLDL (−95%). These results suggest that lipoprotein lipase may enhance the uptake process beyond its role in lipolytic remodelling but does not appear to be an absolute requirement. In contrast, heparin had no effect on LDL-mediated cholesterol ester accumulation. Lactoferrin, which inhibits interaction with the low density lipoprotein receptor-related protein (LRP), was also very effective at inhibiting HTg-VLDL increases in intracellular cholesterol ester (− 95% ± 6%, P < 0.01). However, there was no effect of either heparin or lactoferrin on HTg-VLDL-mediated triglyceride accumulation. Thus cell surface heparin sulphate may facilitate intracellular lipid acquisition by providing a stabilizing bridge with the lipoproteins and enhance uptake through receptor-mediated processes such as LRP.     

PCSK9 and resistin at the crossroads of the atherogenic dyslipidemia

The atherogenic dyslipidemia is a pathophysiological lipid triad, composed of high triglycerides and low-density lipoprotein and low high-density lipoprotein. The dyslipidemia is highly prevalent in individuals who are obese, insulin resistant and those with Type 2 diabetes and is the major contributing factor to the high atherosclerotic cardiovascular disease risk in these subjects. The primary initiating event in atherogenic dyslipidemia development is the hepatic overproduction of very-low-density lipoprotein (VLDL). The intracellular and extracellular protein triggers of hepatic VLDL production were not known until the recent identification of the causal roles of PCSK9 and resistin. Both PCSK9 and resistin act in large part by targeting and reducing the hepatic degradation of VLDL apoB through distinctly different mechanisms. In the current review, we discuss both the individual roles and the interaction of these proteins in driving atherogenic dyslipidemia, and thus, atherosclerotic cardiovascular disease progression in humans. We further explore the important therapeutic implications of these findings.