High-monounsaturated fatty acid diets lower both plasma cholesterol and triacylglycerol concentrations.
(25/1157)
BACKGROUND: Low-fat diets increase plasma triacylglycerol and decrease HDL-cholesterol concentrations, thereby potentially adversely affecting cardiovascular disease (CVD) risk. High-monounsaturated fatty acid (MUFA), cholesterol-lowering diets do not raise triacylglycerol or lower HDL cholesterol, but little is known about how peanut products, a rich source of MUFAs, affect CVD risk. OBJECTIVE: The present study compared the CVD risk profile of an Average American diet (AAD) with those of 4 cholesterol-lowering diets: an American Heart Association/National Cholesterol Education Program Step II diet and 3 high-MUFA diets [olive oil (OO), peanut oil (PO), and peanuts and peanut butter (PPB)]. DESIGN: A randomized, double-blind, 5-period crossover study design (n = 22) was used to examine the effects of the diets on serum lipids and lipoproteins: AAD [34% fat; 16% saturated fatty acids (SFAs), 11% MUFAs], Step II (25% fat; 7% SFAs, 12% MUFAs), OO (34% fat; 7% SFAs, 21% MUFAs), PO (34% fat; 7% SFAs, 17% MUFAs), and PPB (36% fat; 8% SFAs, 18% MUFAs). RESULTS: The high-MUFA diets lowered total cholesterol by 10% and LDL cholesterol by 14%. This response was comparable with that observed for the Step II diet. Triacylglycerol concentrations were 13% lower in subjects consuming the high-MUFA diets and were 11% higher with the Step II diet than with the AAD. The high-MUFA diets did not lower HDL cholesterol whereas the Step II diet lowered it by 4% compared with the AAD. The OO, PO, and PPB diets decreased CVD risk by an estimated 25%, 16%, and 21%, respectively, whereas the Step II diet lowered CVD risk by 12%. CONCLUSION: A high-MUFA, cholesterol-lowering diet may be preferable to a low-fat diet because of more favorable effects on the CVD risk profile. (+info)
Effects of the gap junction uncoupler palmitoleic acid on the activation and repolarization wavefronts in isolated rabbit hearts.
(26/1157)
1. The heart normally acts as an electrical syncytium coupled via gap junctional channels. Since closure of these channels has been considered arrhythmogenic, we wanted to elucidate, how activation and repolarization wavefronts are altered during progressive pharmacological gap junctional uncoupling. 2. We used the well known gap junction uncoupler palmitoleic acid (PA). The specificity of PA was tested in rabbit papillary muscles, which exhibited slowed conduction without affecting action potential morphology. We submitted isolated rabbit hearts (Langendorff-technique) to increasing concentrations of palmitoleic acid (0.2, 1, 2, 5, 10, 20 microM), while 256 channel epicardial potential mapping was carried out. 3. In presence of PA activation recovery intervals (ARI) at the 256 electrodes became highly inhomogeneous with a dramatic increase in the dispersion of activation recovery intervals (from 6 to 35 ms, P>0.01; EC50=7 microM), while the mean ARI-duration at 256 sites remained stable. PA led to marked alterations of the activation pattern, expressed as percentage of unchanged activation vectors (reduction from 32 to 10%, P<0.01, EC50=3.3 microM), to prolongation of atrioventricular conduction time (from 58 to 107 ms, P<0.01; EC50=8 microM) of total activation time (from 7 to 14 ms, P<0.05, EC50=11 microM) and of QRS-complex-duration. 4. In additional experiments the ventricle was paced via a bipolar electrode during the mapping procedure. From the isochrones longitudinal and transversal velocities were assessed showing that PA reduced transversal conduction velocity more distinctly than longitudinal. 5. With regard to maximum effects and EC50 values we conclude that gap junction uncoupling by PA mainly affects atrioventricular conduction, ARI-dispersion and ventricular activation pattern. As important arrhythmogenic effects of uncoupling enhancement of dispersion with concomitant disturbation of the normal activation pattern and slowing of conduction might be considered. (+info)
LPD lipopolyplex initiates a potent cytokine response and inhibits tumor growth.
(27/1157)
Our laboratory has recently developed a lipopolyplex consisting of DOTAP:cholesterol liposomes, protamine sulfate, and plasmid DNA (LPD) that provides improved systemic gene delivery compared with lipoplex following tail vein injection in mice. Because endothelial cells are the primary cells transfected in the lung, it was hypothesized that LPD might be an effective vector for gene therapy of pulmonary metastases. This hypothesis was examined by testing the efficacy of cytokine (IL-12) and tumor suppressor (p53) strategies for treatment of an experimental model of pulmonary metastasis in C57Bl/6 mice. Surprisingly, all LPD complexes including those containing an 'empty' plasmid provided a potent (>50% inhibition) and dose-dependent antitumor effect, compared with dextrose-treated controls. In addition, i.v. injections of LPD containing 'empty' plasmid also inhibited tumor growth in a subcutaneous model of C3 fibrosarcomma. The antitumor effect correlated well with a strong and rapid proinflammatory cytokine (TNF-alpha, IL-12 and IFN-gamma) response. Naked plasmid DNA did not elicit a cytokine response and the response required assembly of DNA into a lipoplex or the LPD lipopolyplex. Except for the heart, elevated levels of cytokine were observed in all organs (lung, liver, kidney and spleen) where LPD is known to have gene transfer activity. Methylation of immune-stimulatory CpG motifs in the plasmid component of LPD inhibited the proinflammatory cytokine response as well as the antitumor effect of LPD in both tumor systems. This suggests that i. v. administration of LPD elicits a systemic proinflammatory cytokine response that mediates the antitumor activity of the lipopolyplex. In addition, the antitumor activity was not observed in SCID mice suggesting a possible role for B or T lymphocytes in the antitumor response initiated by LPD. This represents the first demonstration that an intravenously administered cationic liposome-based nonviral vector can promote a systemic, Th1-like innate immune response. The immune adjuvant properties of LPD might prove to be suitable for delivering tumor-specific antigens in the context of DNA vaccination. (+info)
Differences in glucose-dependent insulinotrophic polypeptide hormone and hepatic lipase in subjects of southern and northern Europe: implications for postprandial lipemia.
(28/1157)
BACKGROUND: This study was an extension of a previous study that showed different lipemic responses to standard test meals in subjects from southern and northern Europe. OBJECTIVE: The aim was to determine in 32 healthy young men from northern and southern Europe whether differences in the secretion of insulin and glucose-dependent insulinotrophic polypeptide (GIP) might explain these findings through the actions of these hormones on lipoprotein lipase. DESIGN: We investigated in a randomized, single-blind, crossover study the effects of 2 test meals of identical macronutrient composition but different saturated fatty acid (SFA) and monounsaturated fatty acid (MUFA) contents on postprandial GIP, insulin, the ratio of incremental triacylglycerol to apolipoprotein B-48 (a marker of chylomicron size), and the activity of postheparin lipases. RESULTS: Fasting and postprandial GIP concentrations and postheparin hepatic lipase activities were significantly higher in the southern Europeans (P < 0.001 and P < 0.02, respectively). Lipoprotein lipase activity after the SFA-rich meal was significantly higher in the northern Europeans (P < 0.01). HL activity 9 h after the SFA-rich meal and the area under the curve (AUC) for the postprandial insulin response correlated with the AUC for the postprandial GIP response [r = 0.44 (P < 0.04) and r = 0.46 (P < 0.05), respectively]. There were no significant differences in chylomicron size between the 2 groups for either meal, but when the groups were combined there was a significant difference in chylomicron size between the SFA- and MUFA-rich meals (P < 0.05), which could be due to the formation of larger chylomicrons after the MUFA-rich meal. CONCLUSION: The significantly higher GIP and insulin responses and HL activities in southern Europeans may provide an explanation for our previous report of attenuated postprandial triacylglycerol and apolipoprotein B-48 responses in them. (+info)
Regulation of vascular smooth muscle cell proliferation by nuclear factor-kappaB and its inhibitor, I-kappaB.
(29/1157)
Proliferation of vascular smooth muscle cells (SMC) is a crucial event in the formation of atherosclerotic tissues and is regulated by nuclear transcriptional factors including nuclear factor-kappaB (NF-kappaB). We constructed a reporter gene assay to measure NF-kappaB-dependent transcriptional activity in SMC. Thrombin receptor-activating peptide (TRAP) and basic fibroblast growth factor (bFGF) stimulated SMC proliferation and rapidly enhanced the NF-kappaB transcriptional activity in a dose-dependent manner. 4-Cyano-5,5-bis-(methoxyphenyl)4-pentenoic acid (E5510) significantly inhibited SMC proliferation and also suppressed NF-kappaB transcription stimulated by TRAP and bFGF. In contrast, although tumor necrosis factor (TNF)-alpha activated NF-kappaB transcription, E5510 had no effect on TNF-alpha-induced activation. NF-kappaB was activated after the stimulation of TRAP, bFGF, and TNF-alpha in electrophoretic mobility shift assay, and E5510 suppressed the NF-kappaB activation induced by TRAP and bFGF but not the activation by TNF-alpha. Western blot analysis of I-kappaBalpha and I-kappaBbeta, inhibitors of NF-kappaB, indicated that I-kappaBalpha degradation, rather than I-kappaBbeta degradation, was important in NF-kappaB activation after the stimulation of TRAP and bFGF. PD98059, an inhibitor of extracellular signal-regulated kinase (ERK) kinase, suppressed NF-kappaB transcriptional activity and SMC proliferation. The phosphorylation of ERK1/2 was rapidly induced by TRAP and bFGF but not by TNF-alpha. These results indicate that TRAP and bFGF induced I-kappaB degradation and NF-kappaB activation through a distinct pathway from TNF-alpha and that ERK1/2 may play an important role in NF-kappaB activation induced by TRAP and bFGF. (+info)
Interactions between angiotensin-I converting enzyme insertion/deletion polymorphism and response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin: the lipoprotein and coronary atherosclerosis study.
(30/1157)
OBJECTIVES: Our objectives were to determine whether angiotensin-1 converting enzyme (ACE) insertion/deletion (I/D) polymorphism was associated with the severity of coronary artery disease (CAD) and its progression/regression in response to fluvastatin therapy in the Lipoprotein and Coronary Atherosclerosis Study (LCAS) population. BACKGROUND: Genetic factors are involved in susceptibility to CAD. Angiotensin-1 converting enzyme I/D polymorphism, which accounts for half of the variance of plasma and tissue levels of ACE, has been implicated in susceptibility to CAD and myocardial infarction (MI). METHODS: Angiotensin-1 converting enzyme genotypes were determined by polymerase chain reaction (PCR). Fasting plasma lipids were measured and quantitative coronary angiograms were obtained at baseline and 2.5 years following randomization to fluvastatin or placebo. RESULTS: Ninety-one subjects had DD, 198 ID and 75 II genotypes. The mean blood pressure, minimum lumen diameter (MLD), number of coronary lesions and total occlusions were not significantly different at baseline or follow-up among the genotypes. There was a significant genotype-by-treatment interaction for total cholesterol (p = 0.018), low-density lipoprotein cholesterol (LDL-C) (p = 0.005) and apolipoprotein (apo) B (p = 0.045). In response to fluvastatin therapy, subjects with DD, compared with those with ID and II genotypes, had a greater reduction in total cholesterol (19% vs. 15% vs. 13%), LDL-C (31% vs. 25% vs. 21%) and apo B (23% vs. 15% vs. 12%). Definite progression was less (14%) and regression was more common (24%) in DD as compared with those with ID (32% and 17%) and II (33% and 3%) genotypes (p = 0.023). Changes in the mean MLD and lesion-specific MLD also followed the same trend. CONCLUSIONS: Angiotensin-1 converting enzyme I/D polymorphism is associated with the response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin. Subjects with DD genotype had a greater reduction in LDL-C, a higher rate of regression and a lower rate of progression of CAD. (+info)
Comparison between cationic polymers and lipids in mediating systemic gene delivery to the lungs.
(31/1157)
Airway inflammation frequently found in congenital and acquired lung diseases may interfere with gene delivery by direct administration through either instillation or aerosol. Systemic delivery by the intravenous administration represents an alternative route of delivery that might bypass this barrier. A nonviral approach for transfecting various airway-derived cell lines in vitro showed that cationic polymers (PEI 22K and 25K) and lipids (DOTAP, GL-67/DOPE) are able to transfect with high efficiency the reporter genes firefly luciferase and E. coli lacZ. Notably, two properties predicted that cationic vectors would be useful for a systemic gene delivery approach to the lung: (1) transfection was not inhibited or increased when cells were incubated with cationic lipids or polymers in the presence of serum; and (2) cationic vectors protected plasmid DNA from DNase degradation. A single injection of DNA complexed to the cationic polymer PEI 22K into the tail vein of adult mice efficiently transfected primarily the lungs and to a lesser extent, heart, spleen, kidney and liver. The other vectors mediated lower to undetectable levels of luciferase expression in the lungs, with DOTAP > GL67/DOPE > PEI 25K > DOTMA/DOPE. A double injection protocol with a 15-min interval between the two doses of DOTAP/DNA complexes was investigated and showed a relevant role of the first injection in transfecting the lungs. A two log increase in luciferase expression was obtained either when the two doses were comprised of luciferase plasmid or when an irrelevant plasmid was used in the first injection. The double injection of luciferase/PEI 22K complexes determined higher transgene levels than a single dose, but a clear difference using an irrelevant plasmid as first dose was not observed. Using lacZ as a reporter gene, it was shown that only cells in the alveolar region, including type II penumocytes, stained positively for the transgene product. (+info)
A new liposomal formulation for antisense oligodeoxynucleotides with small size, high incorporation efficiency and good stability.
(32/1157)
Antisense oligodeoxynucleotides (asODN) are therapeutic agents that are designed to inhibit the expression of disease-related genes. However, their therapeutic use may be hindered due to their rapid clearance from blood and their inefficiency at crossing cell membranes. Cationic liposome complexes have been used to enhance the intracellular delivery of asODN in vitro; however, this type of carrier has unfavorable pharmacokinetics for most in vivo applications. Significant therapeutic activity of cationic liposomal asODN following systemic administration has not been demonstrated. In an effort to develop improved liposomal carriers for asODN for in vivo applications, we have evaluated the physical characteristics of two formulations which represent alternatives to cationic liposome-asODN complexes: asODN passively entrapped within neutral liposomes (PELA) and asODN formulated in a novel coated cationic liposomal formulation (CCL). Our results confirm that PELA can be extruded to small diameters that are suitable for intravenous administration. PELA are stable in human plasma; however, the incorporation efficiency is relatively low ( approximately 20%). The CCL formulation can also be extruded to small diameters (<200 nm), with significantly higher (80-100%) incorporation efficiency and are stable in 50% human plasma at 37 degrees C. A liposomal carrier for asODN with these characteristics may provide a significant therapeutic advantage over free asODN for some therapeutic applications. (+info)