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PubMed2003

Ginkgo biloba extract inhibits tumor necrosis factor-alpha-induced reactive oxygen species generation, transcription factor activation, and cell adhesion molecule expression in human aortic endothelial cells.

OBJECTIVE: This study was conducted to examination whether Ginkgo biloba extract (GBE), a Chinese herb with antioxidant activity, could reduce cytokine-induced monocyte/human aortic endothelial cell (HAEC) interaction, a pivotal early event in atherogenesis. METHODS AND RESULTS: Pretreatment of HAECs with GBE (50 and 100 microg/mL for 18 hours) significantly suppressed cellular binding between the human monocytic cell line U937 and tumor necrosis factor-alpha (TNF-alpha)-stimulated HAECs by using in vitro binding assay (68.7% and 60.1% inhibitions, respectively). Cell enzyme-linked immunosorbent assay and immunoblot analysis showed that GBE (50 microg/mL for 18 hours) significantly attenuated TNF-alpha-induced cell surface and total protein expression of vascular cellular adhesion molecule-1 and intracellular adhesion molecule-1 (63.5% and 69.2%, respectively; P<0.05). However, pretreatment with probucol (5 micromol/L for 18 hours) reduced the expression of vascular cellular adhesion molecule-1 but not intracellular adhesion molecule-1. Preincubation of HAECs with GBE or probucol significantly reduced intracellular reactive oxygen species formation induced by TNF-alpha (76.8% and 68.2% inhibitions, respectively; P<0.05). Electrophoretic mobility shift assay demonstrated that both GBE and probucol inhibited transcription factor nuclear factor-kappaB activation in TNF-alpha-stimulated HAECs (55.2% and 65.6% inhibitions, respectively) but only GBE could inhibit the TNF-alpha-stimulated activator protein 1 activation (45.1% inhibition, P<0.05). CONCLUSIONS: GBE could reduce cytokine-stimulated endothelial adhesiveness by downregulating intracellular reactive oxygen species formation, nuclear factor-kappaB and activator protein 1 activation, and adhesion molecule expression in HAECs, supporting the notion that the natural compound Ginkgo biloba may have potential implications in clinical atherosclerosis disease.

Aorta↗
PubMed2000

Carvedilol for prevention of restenosis after directional coronary atherectomy : final results of the European carvedilol atherectomy restenosis (EUROCARE) trial.

BACKGROUND: In addition to its known properties as a competitive, nonselective beta and alpha-1 receptor blocker, carvedilol directly inhibits vascular myocyte migration and proliferation and exerts antioxidant effects that are considerably greater than those of vitamin E or probucol. This provides the basis for an evaluation of carvedilol for the prevention of coronary restenosis. METHODS AND RESULTS: In a prospective, double-blind, randomized, placebo-controlled trial, 25 mg of carvedilol was given twice daily, starting 24 hours before scheduled directional coronary atherectomy and continuing for 5 months after a successful procedure. The primary end point was the minimal luminal diameter as determined during follow-up angiography 26+/-2 weeks after the procedure. Of 406 randomized patients, 377 underwent attempted atherectomy, and in 324 (88.9%), a </=50% diameter stenosis was achieved without the use of a stent. Evaluable follow-up angiography was available in 292 eligible patients (90%). No differences in minimal luminal diameter (1.99+/-0.73 mm versus 2.00+/-0.74 mm), angiographic restenosis rate (23.4% versus 23.9%), target lesion revascularization (16.2 versus 14.5), or event-free survival (79.2% versus 79.7%) between the placebo and carvedilol groups were observed at 7 months. CONCLUSIONS: The maximum recommended daily dose of the antioxidant and beta-blocker carvedilol failed to reduce restenosis after successful atherectomy. These findings are in contrast to those of the Multivitamins and Probucol Trial, which raises doubts regarding the validity of the interpretation that restenosis reduction by probucol was via antioxidant effects. The relationship between antioxidant agents and restenosis remains to be elucidated.

Adrenergic Antagonists↗
PubMed1991

Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein.

Incubation of cocultures of human aortic endothelial (HAEC) and smooth muscle cells (HASMC) with LDL in the presence of 5-10% human serum resulted in a 7.2-fold induction of mRNA for monocyte chemotactic protein 1 (MCP-1), a 2.5-fold increase in the levels of MCP-1 protein in the coculture supernatants, and a 7.1-fold increase in the transmigration of monocytes into the subendothelial space of the cocultures. Monocyte migration was inhibited by 91% by antibody to MCP-1. Media collected from the cocultures that had been incubated with LDL induced target endothelial cells (EC) to bind monocyte but not neutrophil-like cells. Media collected from cocultures that had been incubated with LDL-induced monocyte migration into the subendothelial space of other cocultures that had not been exposed to LDL. In contrast, media from separate cultures of EC or smooth muscle cells (SMC) containing equal number of EC or SMC compared to coculture and incubated with the same LDL did not induce monocyte migration when incubated with the target cocultures. High density lipoprotein HDL, when presented to cocultures together with LDL, reduced the increased monocyte transmigration by 91%. Virtually all of the HDL-mediated inhibition was accounted for by the HDL2 subfraction. HDL3 was essentially without effect. Apolipoprotein AI was also ineffective in preventing monocyte transmigration while phosphatidylcholine liposomes were as effective as HDL2 suggesting that lipid components of HDL2 may have been responsible for its action. Preincubating LDL with beta-carotene or with alpha-tocopherol did not reduce monocyte migration. However, pretreatment of LDL with probucol or pretreatment of the cocultures with probucol, beta-carotene, or alpha-tocopherol before the addition of LDL prevented the LDL-induced monocyte transmigration. Addition of HDL or probucol to LDL after the exposure to cocultures did not prevent the modified LDL from inducing monocyte transmigration in fresh cocultures. We conclude that cocultures of human aortic cells can modify LDL even in the presence of serum, resulting in the induction of MCP-1, and that HDL and antioxidants prevent the LDL induced monocyte transmigration.

Antioxidants↗
PubMed1995

Beta-carotene inhibits atherosclerosis in hypercholesterolemic rabbits.

Oxidatively damaged LDL may be of central importance in atherogenesis. Epidemiological evidence suggests that high dietary intakes of beta-carotene and vitamin E decreases the risk for atherosclerotic vascular disease, raising the possibility that lipid-soluble antioxidants slow vascular disease by protecting LDL from oxidation. To test this hypothesis, we fed male New Zealand White rabbits a high-cholesterol diet or the same diet supplemented with either 1% probucol, 0.01% vitamin E, 0.01% all-trans beta-carotene, or 0.01% 9-cis beta-carotene; then we assessed both the susceptibility of LDL to oxidation ex vivo and the extent of aortic atherosclerosis. As in earlier studies, probucol protected LDL from oxidation and inhibited lesion formation. In contrast, vitamin E modestly inhibited LDL oxidation but did not prevent atherosclerosis. While beta-carotene had no effect on LDL oxidation ex vivo, the all-trans isomer inhibited lesion formation to the same degree as probucol. Moreover, all-trans beta-carotene was undetectable in LDL isolated from rabbits fed the compound, although tissue levels of retinyl palmitate were increased. The effect of all-trans beta-carotene on atherogenesis can thus be separated from the resistance of LDL to oxidation, indicating that other mechanisms may account for the ability of this compound to prevent vascular disease. Our results suggest that metabolites derived from all-trans beta-carotene inhibit atherosclerosis in hypercholesterolemic rabbits, possibly via stereospecific interactions with retinoic acid receptors in the artery wall.

Animals↗
PubMed1983

Comparative study of four hypolipidaemic agents on the activity of drug-metabolizing enzymes in rat liver microsomes.

In order to understand the secondary effects of hypolipidaemic agents in human therapy, the authors have studied the inductive properties of four of these drugs, clofibrate, F1379, fenofibrate and probucol, on hepatic drug metabolizing enzymes in the rat. Each hypolipidaemic molecule was administered once a day for five days at doses ranging from 100 to 450 mg/kg/day. All the drugs tested caused hepatomegaly, the effect being particularly marked in the case of F1379 and fenofibrate; on the other hand they decreased the microsomal protein content, especially after F1379 or probucol treatment. Cytochrome P-450 concentration was not greatly affected, with only a 40% increase by clofibrate (dose 200 mg/kg/day) and by F1379 at the lower dose. It is of interest that all the hypolipidaemic agents tested enhanced the activity of epoxide hydrolase with 4, 5 benzo(a)pyrene oxide as the substrate. Except for fenofibrate and probucol at the lower dose, they all strongly increased the activity. The greatest change was effected by F1379 which led to a three to eight-fold increase over the control values. We also measured UDP-glucuronosyltransferase activities using two substrates belonging to group I (4-nitrophenol) and group II (4-hydroxybiphenyl). It appears that the changes in enzyme activity found depended both on the type and the dose of the drug administered and on the chemical structure of the substrate. This study showed that hypolipidaemic drugs which are chemically related to clofibrate could greatly modify the activity of drug metabolizing enzymes and therefore alter the transformation of drugs administered concomitantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Clofibrate and di(2-ethylhexyl)phthalate increase ubiquinone contents without affecting cholesterol levels.

Induction studies were performed on liver, muscle, heart, brain and blood by feeding Sprague-Dawley rats a diet containing a peroxisome proliferator, clofibrate or di(2-ethylhexyl)phthalate. Ingestion of these drugs resulted in an increase in the amount of two different types of ubiquinone homologues UQ9 and UQ10 found in rat. Phthalate proved to be the more effective drug, leading to a highly increased amount of ubiquinone in the liver. Increases were also found in all the above-mentioned organs except the brain. The UQ9 levels were raised to 400, 200, 120 and 120%, of the respective normal values. The antioxidant and hypolipidemic agent, probucol, was used as a control to evaluate whether the increased ubiquinone level constituted a response to the elevated hydrogen peroxide pressure, resulting from the induced increase in fatty acid beta-oxidation. In the presence of probucol, ubiquinone levels were decreased in all the above-mentioned organs except heart and brain. Probucol had limited effects on the amount of cholesterol and did not significantly alter the amount of dolichol. The two peroxisome proliferators differed in their effects on cholesterol, as well as on dolichol levels which was induced by phthalate but not by clofibrate. The possible mechanisms involved, and the importance of low toxicity drugs which could elevate ubiquinone levels in various tissues, are discussed.

Animals↗
PubMed2005

Anthocyanins increase low-density lipoprotein and plasma cholesterol and do not reduce atherosclerosis in Watanabe Heritable Hyperlipidemic rabbits.

Anthocyanin-rich beverages have shown beneficial effects on coronary heart disease in epidemiological and intervention studies. In the present study, we investigated the effect of black currant anthocyanins on atherosclerosis. Watanabe Heritable Hyperlipidemic rabbits (n = 61) were fed either a purified anthocyanin fraction from black currants, a black currant juice, probucol or control diet for 16 weeks. Purified anthocyanins significantly increased plasma cholesterol and low-density lipoprotein (LDL) cholesterol. Intake of black currant juice had no effect on total plasma cholesterol, but lowered very-low-density lipoprotein (VLDL) cholesterol significantly. There were no significant effects of either purified anthocyanins or black currant juice on aortic cholesterol or development of atherosclerosis after 16 weeks. Probucol had no effect on plasma cholesterol but significantly lowered VLDL-cholesterol and decreased aortic cholesterol accumulation. The erythrocyte antioxidant enzyme glutathione peroxidase was significantly increased by purified anthocyanins and superoxide dismutase was increased by both anthocyanin-containing treatments. Other markers of plasma antioxidant capacity, antioxidant enzymes, protein and lipid oxidation were not affected by any of the anthocyanin treatments. Adverse effects of purified anthocyanins were observed on plasma- and LDL-cholesterol. These effects were not observed with black currant juice, suggesting that black currants may contain components reducing the adverse effects of anthocyanins.

Animals↗
PubMed2004

Antioxidant role of human haptoglobin.

Human plasma haptoglobin (Hp) is classified according to three phenotypes: Hp 1-1, 2-1, and 2-2 attributed by their two common alleles 1 and 2. Clinically, the 2-2 phenotype is associated with the risk of cardiovascular diseases and diabetes mellitus in patients. In this study, we demonstrate that Hp is an extremely potent antioxidant, which directly protects low density lipoprotein from Cu(2+)-induced oxidation. Its potency was markedly superior to probucol (one of the most potent antioxidants). Ranking of the IC(50) of antioxidant activity was as follows: Hp 1-1 greater, similar Hp 2-1 greater, similar Hp 2-2 greater, similar probucol greater, similar vitamin E. Blockage of disulfide linkages between Hp subunits, not only abolished the alpha-helical content but also diminished the ability of Hp to form a complex with hemoglobin. The modified Hp subunits exerted almost 4 times greater antioxidant activity than that of native Hp. To investigate the antioxidant role of Hp on the cellular level, the cDNA of Hp 1-1 was cloned, introduced into the pcDNA3.0 vector which contains the cytomega lovirus promoter and transfected into chinese hamster ovary (CHO)-K1 cells. Following transfection, CHO cells were able to express Hp 1-1 protein and significantly (p < 0.001) elevated cell tolerance against oxidative stress. Transfected cells showed 2-fold higher resistance to hydrogen peroxide exposure for 24 h compared to control cells. Thus, Hp plays a provocative antioxidant role as demonstrated by our in vitro and ex vivo studies.

Animals↗
PubMed1996

Efficacy of hypochlorous acid scavengers in the prevention of protein carbonyl formation.

We observed that protein (bovine serum albumin) carbonyl content increases upon hypochlorite oxidation, and this increase is inhibited in a concentration-dependent manner in the presence of hypochlorite scavengers. Based on this observation, we tested whether some known hypochlorite scavengers (lipoic acid, cysteine, and glutathione) and some other antioxidants (uric acid, ascorbic acid, alpha-tocopherol, and probucol) could prevent protein carbonyl formation. N-acetylcysteine, dihydrolipoic acid, cysteine, and glutathione (reduced form, GSH), which otherwise could not be tested in a previously reported 5-thio-2-nitrobenzoic acid test system, were successfully evaluated in our assay. The hypochlorite scavenging capacity of different compounds, compared by determining the IC50 (concentration which produces 50% inhibition), showed that the compounds tested have the following potency: dihydrolipoic acid > GSH, N-acetylcysteine > cysteine > S-methyl glutathione > lipoic acid, ascorbic acid > cystine, GSSG, and uric acid. No scavenging ability was observed for either alpha-tocopherol or probucol.

Animals↗
PubMed2001

Antioxidant therapy attenuates JNK activation and apoptosis in the remote noninfarcted myocardium after large myocardial infarction.

We hypothesized that the concomitant occurrence of increased oxidative stress, JNK activation, and myocyte apoptosis in the remote myocardium (RM) following a large myocardial infarction (MI) are causally related. Three days following coronary ligation, rats were randomized to treatment with probucol and PDTC (MI-T) or vehicle (MI). Control rats (C) underwent sham operation. At 7 weeks, TBARS assay showed increased level of lipid-peroxidation within the RM in the MI group vs C, which was completely inhibited in the MI-T group. Similarly, Western blot analysis showed a twofold increase in p-JNK in the MI group, vs C, which was attenuated in MI-T, a result confirmed by a JNK-kinase activity. Furthermore, apoptosis was increased within the RM in MI vs C, while this was inhibited in MI-T. We conclude that long-term antioxidant therapy with probucol and PDTC attenuates oxidative stress, JNK activation, and myocyte apoptosis within the RM after large MI.

Animals↗
PubMed1992

Ascorbate and phenolic antioxidant interactions in prevention of liposomal oxidation.

Efficient prevention of membrane lipid peroxidation by vitamin E (alpha-tocopherol) may involve its regeneration by vitamin C (ascorbate). Conceivably, the efficacy of antioxidants designed as therapeutic agents could be enhanced if a similar regeneration were favorable; thus, a model membrane system was developed which allowed assessment of interaction of phenolic antioxidants with ascorbate and ascorbyl-6-palmitate. Ascorbate alone (50-200 microM) potentiated oxidation of soybean phosphatidylcholine liposomes by Fe2+/histidine-Fe3+, an effect which was temporally related to reduction of Fe3+ generated during oxidation. Addition of 200 microM ascorbate to alpha-tocopherol-containing liposomes (0.1 mol%) resulted in marked, synergistic protection. Accordingly, in the presence but not absence of ascorbate, alpha-tocopherol levels were maintained relatively constant during Fe2+/histidine-Fe3+ exposure. Probucol (4,4'-[(1-methylethylidine)bis(thio)]bis[2,6-bis(1,1- dimethylethyl)]phenol), an antioxidant which prevents oxidation of low density lipoproteins, and its analogues MDL 27,968 (4,4'-[(1-methylethylidene)bis(thio)]bis[2,6- dimethyl]phenol) and MDL 28,881 (2,6-bis(1,1-dimethylethyl)-4-[(3,7,11- trimethyldodecyl)thio]phenol) prevented oxidation but exhibited no synergy with ascorbate. Ascorbyl-6-palmitate itself was an effective antioxidant but did not interact synergistically with any of the phenolic antioxidants. Differential scanning calorimetry revealed significant differences among the antioxidants in their effect on the liquid-crystalline phase transition of dipalmitoyl phosphatidylcholine (DPPC) liposomes. Both alpha-tocopherol and MDL 27,968 significantly reduced the phase transition temperature and the enthalpy of the transition. MDL 28,881 had no effect while probucol was intermediate. The potential for ascorbate or its analogues to interact with phenolic antioxidants to provide a more effective antioxidant system appears to be dictated by structural features and by the location of the antioxidants in the membrane.

Antioxidants↗
PubMed2006

Induction of adiponectin in skeletal muscle of type 2 diabetic mice: In vivo and in vitro studies.

AIMS/HYPOTHESIS: Adiponectin is an adipokine that exhibits insulin-sensitising, fat-burning and anti-inflammatory properties as well as modulatory effects on oxidative stress. We examined whether adiponectin could be induced in a non-adipose tissue, skeletal muscle, in response to metabolic or oxidative aggression both in vivo (in a murine model of type 2 diabetes) and in vitro. METHODS: Obese and diabetic ob/ob mice were used and compared with lean littermates. Some obese mice were treated with the antioxidant probucol for 3 weeks. At the end of the experiment, blood was sampled and tibialis anterior muscles were collected for mRNA measurement and immunohistochemistry. Additional in vitro experiments were performed on C2C12 myotubes cultured for up to 48 h. RESULTS: In spite of hypoadiponectinaemia, Adipoq mRNA levels were markedly increased in the skeletal muscle of ob/ob mice and correlated with systemic oxidative stress. Adipoq upregulation was shown in laser-microdissected myocytes of obese mice. Concomitantly, immunoreactivity for adiponectin was enhanced in obese muscle fibres together with lipid infiltration and local markers of oxidative stress. In cultured C2C12 myotubes, a triglyceride mix and reactive oxygen species producers (H2O2 or a lipoperoxidation end-product) upregulated Adipoq expression and adiponectin production. This effect was reversed by an antioxidant. Finally, treatment of obese mice with probucol also attenuated upregulation in muscle. CONCLUSIONS/INTERPRETATION: The paradoxical upregulation of adiponectin in muscle of obese and diabetic mice may result from lipotoxicity and related oxidative stress. This unexpected finding could be viewed as a local protection to counteract ectopic fat deposition and oxidative damage.

Adiponectin↗
PubMed1997

Oxidized lipoproteins found in patients with NIDDM stimulate radical-induced monocyte chemoattractant protein-1 mRNA expression in cultured human endothelial cells.

Although oxidized low density lipoprotein (LDL) exists in plasma from diabetic patients, there are few studies on its biological activity. Thus, we investigated the biological potency of LDL plus intermediate density lipoprotein fraction isolated from 12 non-diabetic and 24 non-insulin-dependent diabetic subjects of similar age and body mass index, in order to induce monocyte chemoattractant protein-1 (MCP-1) mRNA expression in cultured human endothelial cells. MCP-1 mRNA content in the cells exposed to the lipoproteins isolated from the diabetic patients was significantly higher than that from the control subjects (p < 0.001). The increment of MCP-1 mRNA content was positively correlated with not only HbA1c (r = 0.58, p < 0.0001) but also lysophosphatidylcholine (LPC) content in the lipoprotein (r = 0.46, p < 0.005) and was negatively correlated with diene formation lag time as a marker of oxidizability of the lipoprotein (r = -0.33, p < 0.05). Treatments of the cells with either 50 mumol/l probucol, 50 mumol/l alpha-tocopherol, or 0.1 mmol/l deferoxamine suppressed the increase in MCP-1 mRNA content induced by diabetic lipoproteins, respectively. Furthermore, the diabetic lipoproteins activated nuclear transcription factor NF-kappa B in the cells, which was inhibited by pre-treatment of cells with 50 mumol/l probucol. These data indicate that oxidatively modified lipoproteins found in diabetic plasma stimulate MCP-1 gene expression in endothelial cells. The LPC content which reflects oxidative modification of lipoprotein is at least a possible marker of biological activity to increase an atherogenic cytokine in endothelial cells.

Antioxidants↗
PubMed2001

Characterization of simple and reproducible vascular stenosis model in hypercholesterolemic hamsters.

The importance of low-density lipoprotein (LDL) in the etiology of atherosclerosis is well recognized. We have established a reproducible stenosis model in hypercholesterolemic hamsters, and the process of arterial stenosis by thrombus or neointima was studied and compared with that in normal hamsters. The level of plasma LDL was 4.6 times higher in hamsters fed a high-cholesterol diet than in hamsters fed normal food. Endothelial injury in right common carotid arteries was induced using a modified catheter. Arterial blood flow was monitored continuously using a Doppler flow probe. Arterial patency after the initiation of injury in high-cholesterol hamsters was significantly changed as compared with that of normal hamsters. Neointima was observed 2 wk after the vascular injury. The neointimal area of high-cholesterol hamsters was significantly larger than that of normal hamsters. To characterize the stenosis in hypercholesterolemic hamsters, we measured platelet aggregation, thrombin time, activated partial thromboplastin time, and proliferating smooth muscle cells (SMC) in vitro and in vivo. The half-maximal inhibitory concentration value for platelet aggregation induced by thrombin or collagen, the DNA synthesis stimulated by platelet-derived growth factor (PDGF)-BB, and 5-bromo-2-deoxy-uridine labeling indices (proliferating index of SMC in vivo) in high-cholesterol hamsters were each significantly higher than the comparable value from normal hamsters. However, specific binding of PDGF-BB in SMC was not different between the two types of hamsters. Furthermore, we investigated the inhibitory effects of probucol or losartan on neointima formation using this model. Probucol, but not losartan, significantly reduced the neointimal area in hypercholesterolemic hamsters. These findings indicated that high levels of plasma LDL strongly contributed to the development of thrombus and neointima formation via both up-regulation of platelet aggregation and the enhancement of SMC proliferation. This stenosis model may be useful for the investigation of hypercholesterolemia-associated cardiovascular diseases.

Animals↗
PubMed1987

Concomitant induction of cytosolic but not microsomal epoxide hydrolase with peroxisomal beta-oxidation by various hypolipidemic compounds.

The effects of two cholesterol-lowering (probucol and 1-benzyl-imidazole), three triglyceride- and cholesterol-lowering (clofibrate, tiadenol and fenofibrate) and one triglyceride-lowering (acetylsalicylic acid) compounds on the specific activities of two lipid-metabolizing enzymes (cyanide-insensitive peroxisomal beta-oxidation and palmitoyl-CoA hydrolase) and two xenobiotic metabolizing enzymes (cytosolic (cEH) and microsomal epoxide hydrolase (mEHb] from the livers of male Fischer F-344 rats were investigated. With the exception of probucol and acetylsalicylic acid, all compounds tested caused a dose-dependent hepatomegaly. Taken on a weight basis fenofibrate was the most effective inducer, causing a 20-fold induction of peroxisomal beta-oxidation, a 13-fold induction of cEH activity and a 16-fold induction of palmitoyl-CoA hydrolase activity. The other compounds with triglyceride-lowering activity also induced cEH as well as peroxisomal beta-oxidation and palmitoyl-CoA hydrolase activity. The potency of each individual drug was similar for induction of cEH activity as compared with that of peroxisomal beta-oxidation and palmitoyl-CoA hydrolase activity, but very dissimilar for mEHb, which upon treatment with any of the triglyceride-lowering compounds was either not or only minimally (less than 1.5-fold) induced. 1-Benzylimidazole possessing exclusively cholesterol-lowering activity increased mEHb much more than either cEH or peroxisomal beta-oxidation. The absence of an enhancement of cEH activity in in vitro studies confirmed that the increase in enzyme activity by the test compounds is not caused by activation. cEH activity was also induced in the kidney but only about 2-fold by fenofibrate, tiadenol and acetylsalicylic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Oxidized low-density lipoprotein is cytotoxic to human monocyte-macrophages: protection with lipophilic antioxidants.

Human monocyte-macrophages were incubated for 24 h with low-density lipoprotein (LDL) which had been previously oxidized for varying periods up to 24 h with copper ions, in the presence or absence of DL-alpha-tocopherol or probucol. The release of radioactivity from cells preloaded with tritiated adenine was used as an assay of toxicity. Toxicity of oxidized LDL increased with duration of copper oxidation and with increasing evidence of lipid oxidation, measured by assay of thiobarbituric acid-reactive substances and by gas chromatography. Oxidation and toxicity were inhibited by DL-alpha-tocopherol (200 microM) and probucol (50 microM).

Adult↗
PubMed1993

Indications for the presence of circulating peroxidized low density lipoproteins in WHHL rabbits treated with antioxidants.

Low density apolipoprotein (apo) B-100 in homozygous WHHL rabbits appears heterogeneous on SDS-PAGE. At least four high molecular weight apolipoproteins were identified in contrast to the uniform apo B-100 band in the very low density lipoprotein (VLDL) fraction of WHHL-homozygotes and the apo B containing lipoproteins present in WHHL heterozygotes or New Zealand White rabbits. We studied whether these aberrations in homozygote WHHL-LDL were due to physical changes induced by lipid peroxidation. Therefore we treated WHHL rabbits for 28 days with a standard dose of 1% probucol or with a dose of 0.1% vitamin E and studied the parameters indicating lipid peroxidation in circulating LDL and in vitro in relation to its antioxidant content. The LDL of probucol-fed rabbits appeared completely resistant against oxidation in vitro with Cu2+ ions. LDL fluorescence and serum malondialdehyde concentrations, indicators of lipid peroxidized LDL, were lower than in the control WHHL rabbits. LDL of vitamin E-fed WHHL rabbits showed a twofold increased lag phase in comparison with LDL of control-fed animals; the maximal rate of oxidation was 2- to 3-fold lower while LDL fluorescence was between the values obtained in the two other groups. Malondialdehyde concentration in the vitamin E-treated group was also decreased when compared with controls. Despite these indications of increased lipid peroxidized circulating LDL in WHHL controls which could be reversed, at least partially, by the antioxidant treatments applied, these treatments were without effect on the physical structure of LDL as examined with agarose gel electrophoresis. Neither antioxidant treatment changed the typical apo B-100 pattern in WHHL-LDL.

Animals↗
PubMed1992

Inhibition of human low-density lipoprotein oxidation in vitro by Maharishi Ayur-Veda herbal mixtures.

In this study, we examined the effect of the Maharishi Ayur-Veda herbal mixtures (MAHMs) Maharishi Amrit Kalash-4 and -5 (M-4 and M-5), MA-631, and Maharishi Coffee Substitute (MCS) on low-density lipoprotein (LDL) oxidation and compared the potency of these mixtures to ascorbic acid, alpha-tocopherol, and probucol. LDL was incubated in 95% air and 5% CO2, with or without 3 microM Cu(+2), in the presence or absence of MAHMs, for 6 or 24 h. In a separate experiment, LDL was incubated as above except MAHMs were added at 0, 1.5, and 3.5 h after incubation started to assess their effect on initiation and propagation of LDL oxidation. Our results demonstrate that MAHMs caused concentration-dependent inhibition of LDL oxidation as assessed by thiobarbituric acid-reactive substances and electrophoretic mobility. The MAHM showed more antioxidant potency in preventing LDL oxidation than ascorbic acid, alpha-tocopherol, or probucol. Also, MAHMs inhibited both initiation and propagation of cupric ion-catalyzed LDL oxidation. These results suggest the importance of further research on these herbal mixtures in the investigation of atherosclerosis and free radical-induced injury.

Antioxidants↗