Inhibitory effect of tea flavonoids on the ability of cells to oxidize low density lipoprotein.

Dietary flavonoid intake has been reported to be inversely related to mortality from coronary heart disease, and the anti-atherosclerotic effect of flavonoids is considered to be due probably to their antioxidant properties. Oxidation of low density lipoprotein (LDL) has been reported to be induced by the constituent cells of the arterial wall. Accordingly, we examined the effect of pretreatment with tea flavonoids, such as theaflavin digallate, on the ability of cells to oxidize LDL. Theaflavin digallate pretreatment of macrophages or endothelial cells reduced cell-mediated LDL oxidation in a concentration- (0-400 microM) and time- (0-4 hr) dependent manner. This inhibitory effect of flavonoids on cell-mediated LDL oxidation was in the order of theaflavin digallate > theaflavin > or = epigallocatechin gallate > epigallocatechin > gallic acid. Further, we investigated the mechanisms by which flavonoids inhibited cell-mediated LDL oxidation using macrophages and theaflavin digallate. Theaflavin digallate pretreatment decreased superoxide production of macrophages and chelated iron ions significantly. These results suggest that tea flavonoids attenuate the ability of the cell to oxidize LDL, probably by reducing superoxide production in cells and chelating iron ions.

Expression of serum amyloid A protein in the absence of the acute phase response does not reduce HDL cholesterol or apoA-I levels in human apoA-I transgenic mice.

Plasma concentrations of high density lipoprotein (HDL) cholesterol and its major apolipoprotein (apo)A-I are significantly decreased in inflammatory states. Plasma levels of the serum amyloid A (SAA) protein increase markedly during the acute phase response and are elevated in many chronic inflammatory states. Because SAA is associated with HDL and has been shown to be capable of displacing apoA-I from HDL in vitro, it is believed that expression of SAA is the primary cause of the reduced HDL cholesterol and apoA-I in inflammatory states. In order to directly test this hypothesis, we constructed recombinant adenoviruses expressing the murine SAA and human SAA1 genes (the major acute phase SAA proteins in both species). These recombinant adenoviruses were injected intravenously into wild-type and human apoA-I transgenic mice and the effects of SAA expression on HDL cholesterol and apoA-I were compared with mice injected with a control adenovirus. Plasma levels of SAA were comparable to those seen in the acute phase response in mice and humans. However, despite high plasma levels of murine or human SAA, no significant changes in HDL cholesterol or apoA-I levels were observed. SAA was found associated with HDL but did not specifically alter the cholesterol or human apoA-I distribution among lipoproteins. In summary, high plasma levels of SAA in the absence of a generalized acute phase response did not result in reduction of HDL cholesterol or apoA-I in mice, suggesting that there are components of the acute phase response other than SAA expression that may directly influence HDL metabolism.

Effects of soy protein isolate (SPI) and casein on the postprandial lipemia in normolipidemic men.

To elucidate the effects of soybean protein and casein on postprandial lipemia, oral fat load tests were performed before and 3 weeks after the administration of soy protein isolate (SPI) and casein supplement to normolipidemic men. Eleven normolipidemic male subjects on otherwise identical controlled diets were assigned to either a 20 g/d soy protein isolate (SPI) dietary supplement or a casein dietary supplement for three weeks in a crossover design. Fat load tests with 40 g/m2 of bovine milk fat were carried out before and after 3 weeks on the experimental dietary supplements. Fasting plasma concentrations of lipids and apolipoproteins were not significantly different from baseline levels before or after the administration of SPI or casein supplemented diets. Neither SPI nor casein supplement affected the fasting plasma concentrations of lipids and apolipoproteins. The areas under the incremental curve (AUIC) of triglyceride (TG) and remnant-like particles triglyceride (RLP-TG) after both experimental diets were not significantly different from those before the experimental diets. However, the AUIC of remnant-like particles cholesterol (RLP-C) showed a tendency (p = 0.07) to decrease after administration of the diet supplemented with SPI than before the diet. The AUIC of RLP-C was significantly (p < 0.05) lower after the diet supplemented with SPI than after administration of the diet supplemented with casein. These results suggest that 3 weeks of 20 g/d SPI dietary supplement favorably affects the postprandial remnant lipoprotein response as compared to the casein dietary supplement.

Effects of beta-blockers on HMG CoA reductase and LDL receptor activity in cultured human skin fibroblasts.

Previous reports, based on clinical trials and animal experiments, suggest that beta-blockers may be useful in the prevention of atherosclerosis. Betaxolol, a new beta1-selective blocker, was shown to decrease plasma total and LDL cholesterol levels or to have no adverse effect on those [1-4]. While many reports deal with metabolism of triglyceride and high density lipoprotein, fewer publications about cholesterol metabolism are currently available. To clarify the mechanism by which beta-blockers affect lipid metabolism, we examined the effects of beta-blockers on HMG CoA reductase and LDL receptor activity in cultured human skin fibroblasts. L-propranolol, a nonselective beta-blocker, increased HMG CoA reductase activity and decreased LDL receptor activity. However, d-propranolol had no major effects on HMG CoA reductase activity. These results suggest that beta-blockers act on HMG CoA reductase through the beta receptors. Beta1-blocking action should decrease HMG CoA reductase activity and increase LDL receptor activity. In fact, betaxolol, a beta1-selective blocker, decreased HMG CoA reductase activity and increased LDL receptor activity, but metoprolol had no major effect. We speculate that the discrepancy between betaxolol and metoprolol in the effect on HMG CoA reductase and the LDL receptor might be due to the difference of the extent of beta1-selectivity. We conclude that beta1-selective blockers are antihypertensive agents potentially valuable in the prevention of atherosclerosis.

Effect of low-dose simvastatin on cholesterol levels, oxidative susceptibility, and antioxidant levels of low-density lipoproteins in patients with hypercholesterolemia: a pilot study.

In this pilot study, 12 patients (6 men, 6 postmenopausal women) with hypercholesterolemia were treated with low-dose (5 mg/d) simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, for 4 weeks. Low-density lipoprotein (LDL) samples were isolated at the beginning (week 0) and at the end (week 4) of the treatment regimen. Simvastatin caused significant decreases of total cholesterol (-18.1%), LDL cholesterol (-27.6%), and apolipoprotein B (-21.8%), and significantly reduced total cholesterol, free cholesterol, cholesterol esters, phospholipids, and protein in LDL without significantly changing the component ratios and fatty acid levels of LDL. However, simvastatin therapy had no major effects on either antioxidant levels in LDL or the oxidative susceptibility of LDL. We conclude that low-dose simvastatin significantly reduces LDL cholesterol levels without increasing the oxidative susceptibility of LDL or decreasing the antioxidant levels of LDL, and thus may reduce the risk of coronary artery disease.

[Hypertrophic cranial pachymeningitis with propionibacterium acnes detected by dural biopsy].

A 30-year-old woman experienced recurrent dull headache and frequent partial motor seizure (Jacksonian type) that marched from right fingers. This motor seizure was uncontrollable with ordinary anticonvulsant therapy. Cerebrospinal fluid showed mild pleocytosis. Cranial CT examination was unremarkable, but MRI revealed thickened dural lesion on the left fronto-parietal site, giving diagnosis of hypertrophic cranial pachymeningitis. Dural biopsy showed nonspecific chronic granulomatous state without specific granuloma such as tuberculosis nor sarcoidosis. Anaerobic culture revealed Propionibacterium acnes, a rare causative agent of meningitis. We conclude that it is important to follow a case of unknown cause pachymeningitis carefully with MRI, and in some cases, is required a dural biopsy to make a diagnosis before steroid therapy.

Effects of Ca-antagonists on oxidative susceptibility of low density lipoprotein (LDL).

Twelve adults (age 32-61 years) with essential hypertension were recruited from the outpatient clinics of National Defense Medical College hospital to serve as subjects in the present study. They were treated with nilvadipine, a Ca-antagonist, 4 mg b.i.d. for 4 weeks. LDL samples were isolated by ultracentrifugation at the beginning (week 0) and at the end (week 4) of the treatment regimen. The formation of conjugated dienes was measured by incubating 100 micrograms of LDL protein with 2 mumol CuSO4 in 2 ml phosphate buffered saline (PBS). There were no significant differences between lipids levels, composition and anti-oxidant levels of LDL at weeks 0 and 4. The lag time of LDL oxidation was 71.1 +/- 11.3 min at week 0 and 81.3 +/- 13.2 min at week 4 (p < 0.05). In vitro studies of LDL oxidation, evaluated by thiobarbituric acid reactive substances (TBARS) and by agarose electrophoretic mobility, indicated that nilvadipine inhibited the oxidative modification of LDL while amlodipine, used as control, did not. Nilvadipine, a lipophilic Ca-antagonist, significantly prolonged the lag time of conjugated diene formation of LDL by 12.6% but amlodipine, a hydrophilic Ca-antagonist, had no major effect on LDL oxidation. These results suggest that Ca-antagonists are effective for the prevention of atherosclerosis but the effect is dependent upon the lipophilicity of the drugs.