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PubMed2001

Novel galactosylated liposomes for hepatocyte-selective targeting of lipophilic drugs.

Novel galactosylated neutral liposomes containing cholesten-5-yloxy-N-(4-((1-imino-2-beta-D-thiogalactosylethyl)amino)butyl)formamide (Gal-C4-Chol) as a "homing" device were developed for hepatocyte-selective drug targeting. Distearoylphosphatidylcholine (DSPC)/cholesterol (Chol) (60:40) and DSPC/Chol/Gal-C4-Chol (60:35:5) liposomes were prepared and labeled with [3H]cholesteryl hexadecyl ether (CHE). [3H]Prostaglandin E1 (PGE1) and [14C]probucol were incorporated in liposomes as model lipophilic drugs. After intravenous injection of the liposomes, mice were sacrificed at suitable time periods, and the lung, liver, kidney, spleen, and heart were excised. DSPC/Chol/Gal-C4-Chol liposomes rapidly disappeared from the blood, and 85% of the dose had accumulated in the liver within 10 min compared with hepatic accumulation of DSPC/Chol liposomes of 12%. The liver was perfused with collagenase, and liver parenchymal cells (PC) and liver nonparenchymal cells (NPC) were separated by centrifugal differentiation to determine the cellular distribution. The PC/NPC ratios for DSPC/Chol/Gal-C4-Chol and DSPC/Chol liposomes were 15.1 and 1.1, respectively. The hepatic uptake of DSPC/Chol/Gal-C4-Chol liposomes, but not that of DSPC/Chol liposomes, was significantly inhibited by the predosing of galactosylated bovine serum albumin. [14C]Probucol and [3H]PGE1 incorporated in DSPC/Chol/Gal-C4-Chol liposomes was also efficiently delivered to the liver. In conclusion, newly developed galactosylated liposomes have been proven to be a useful carrier for hepatocyte-selective targeting that will have many practical applications.

Animals↗
PubMedDate not supplied

Amelioration of the beta-cell dysfunction in diabetic APA hamsters by antioxidants and AGE inhibitor treatments.

BACKGROUND: In our recent report, probucol treatment ameliorated glucose intolerance and increased the insulin-positive area in the pancreas of streptozotocin (SZ)-induced diabetic APA hamsters. The data suggested that the beneficial effects of probucol treatment on beta-cell function might result from its additive effect as an antioxidant. Here, we examined the antioxidant effects on the beta-cell function in SZ-induced diabetic APA hamsters treated with three different agents, N-acetyl-L-cysteine (NAC), aminoguanidine (AG) and pyridoxamine (PM). METHODS: The control (CB group) and diabetic (SZ group) hamsters were treated with NAC, AG or PM for four weeks from several days after SZ injection. RESULTS: Non-fasting plasma glucose and glycoalbumin levels were significantly reduced in SZ animals by NAC or PM treatment. Glucose tolerance test revealed that fasting plasma glucose levels of SZNAC and SZPM animals were low, similar to the corresponding control animals. Thirty minutes after glucose injection, amelioration in the plasma glucose levels of SZNAC and SZPM animals was observed. Immunohistochemistry revealed that the pancreata of SZNAC, SZAG and SZPM animals showed significantly higher percentages of insulin-positive area than those of non-treated SZ animals. The plasma 8OHdG and malondialdehyde plus 4-hydroxy-2-nonenal (4HNE) levels were significantly decreased especially in SZNAC and SZPM animals. 4HNE-positive cells stained by anti-4HNE antibody were reduced in the islets of each agent-treated animal. SZNAC and SZPM animals showed significantly increased beta-cell proliferation determined by insulin and BrdU double staining. All SZ groups treated with NAC, AG or PM had the high expression levels of Reg and INGAP, which are known to be expressed in regenerating islets. CONCLUSIONS: These data suggest that NAC and PM treatment of SZ-injected diabetic hamsters reduces oxidative stress and restores beta-cell function, but that AG treatment has little beneficial effect on the diabetic conditions of SZ-injected hamsters.

Acetylcysteine↗
PubMed2001

Oxidative stress and functional deficit in diabetic cardiomyopathy.

When the equilibrium between free-radical production and cellular antioxidant defences is disturbed in favour of more free radicals, it causes oxidative stress which can promote cellular injury. Oxidative stress has been suggested to play a role in the pathogenesis of diabetic cardiomyopathy. In streptozotocin-induced diabetes, there is a decrease in antioxidant enzyme activities and an increase in myocardial lipid peroxidation. Probucol, an antioxidant, was found to improve cardiac function which may have been due to an increase in myocardial antioxidant enzyme activities and a decrease in lipid peroxidation in the diabetic animals. Some of the beneficial effects of probucol may also be due to an improvement in plasma insulin levels and a decrease in the plasma glucose. The diabetic state is also associated with endothelial dysfunction, retinopathy, neuropathy and renopathy. Some of these secondary complications may also be mediated by oxidative stress. It is suggested that diabetic cardiomyopathy is associated with an antioxidant deficit and that antioxidant therapy may be useful in improving cardiac function in diabetes.

Animals↗
PubMed1994

Lack of effect of high dose vitamin E on xanthoma regression in homozygous familial hypercholesterolaemia.

There is increasing evidence that oxidative modification of low-density lipoprotein (LDL) plays an important role in the pathogenesis of atherosclerosis. Homozygous familial hypercholesterolaemia (HFH) is characterized by premature, severe atherosclerosis. Drugs available at present are ineffective in lowering the markedly elevated LDL levels in this condition; antioxidant therapy to protect the LDL against oxidation may be of benefit. Probucol, the only drug shown to induce xanthoma regression in HFH, is a potent antioxidant, but it also lowers high-density lipoprotein cholesterol (HDL-C) levels, causing some concern. Vitamin E is a naturally occurring antioxidant that does not affect HDL-C levels. We have therefore evaluated the effect of long-term high dose vitamin E on xanthoma regression in HFH. Ten subjects with HFH, mean age 17 years (range 4-34), received vitamin E (400-1000 mg/dl alpha-tocopherol acetate/day) for a period of 23 months (range 12-27). There was a 4.2-fold increase in the mean serum vitamin E level (mean (S.D.) 49.7 (19.9) to 177.9 (45.6) mumol/l; P < 0.005), but no change in serum lipid or lipoprotein concentrations. Although there was an increase in the in vitro resistance of LDL to oxidation as determined by the duration of the lag phase during copper-mediated oxidation (116 (8.34) vs. 141.5 (9.23) min; P < 0.005) there was no xanthoma regression; in fact they progressed in 4 subjects. Unlike probucol, high dose long-term vitamin E has no demonstrable effect on xanthoma regression in HFH.

Administration, Oral↗
PubMed1995

Effect of vitamin E on atherogenesis in LDL receptor-deficient rabbits.

Vitamin E has been postulated to be antiatherogenic because of its antioxidative potency. However, intervention studies published to date have yielded conflicting results. To assess the antiatherogenic effect of vitamin E, two groups of 10 Watanabe heritable hyperlipidemic (WHHL) rabbits each were fed chow pellets containing D-alpha-tocopherol-acetate at either 40 mg/kg (control group) or 1000 mg/kg (vitamin E group) for 28 weeks. Plasma vitamin E levels in the vitamin E group increased five-fold over those controls (475.5 mumol/l vs. 95.9 mumol/l). The average total plasma cholesterol during the treatment period was not significantly affected by vitamin E (control, 950 +/- 113 mg/dl; vitamin E, 884 +/- 90 mg/dl). Vitamin E treatment had no significant effects on body weights, lipoprotein profiles, or HDL levels. The protection of plasma LDL against oxidation was determined by ex vivo by measuring the lag time in the formation of conjugated dienes in a standardized Cu22+(-)containing system. Lag time in the vitamin E-treated group increased four-fold over that in controls (404 vs. 123 min). The extent of atherosclerosis determined at the end of the study was not significantly different in the two groups (control group, 59.2 +/- 6.0%; vitamin E group, 50.6 +/- 6.2%, P = 0.33). Analysis of the correlation between vitamin E levels and extent of lesions also failed to indicate an antiatherosclerotic effect of vitamin E treatment. We previously reported that an analogue of probucol that provided antioxidative protection similar to that provided by vitamin E failed to prevent atherogenesis in WHHL-rabbits. In contrast probucol conveyed a much greater degree of antioxidant protection and effectively reduced atherosclerosis in rabbits. The results of the present study therefore support the hypothesis that a threshold level of antioxidative protection of LDL may be required to inhibit atherosclerosis.

Animals↗
PubMed1996

Anti-atherosclerotic effect of E5324, an inhibitor of acyl-CoA:cholesterol acyltransferase, in Watanabe heritable hyperlipidemic rabbits.

E5324, n-butyl-N'-[2-[3-(5-ethyl-4-phenyl-1H-imidazol-1-yl)propoxy]-6- methylphenyl]urea, a novel and potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), was evaluated for its anti-atherosclerotic and lipid-lowering effects in Watanabe heritable hyperlipidemic (WHHL) rabbits. At 3 months of age, 40 male WHHL rabbits were divided into 4 groups. The rabbits were fed a standard rabbit chow (control group), or standard rabbit chow containing E5324 (0.1% or 0.02%) or 1% probucol for 16 weeks. Even the high dose of E5324 did not lower the plasma total cholesterol levels throughout the experiment. Probucol slightly reduced the plasma cholesterol levels, and showed anti-atherosclerotic activity, i.e., reductions of atherosclerotic plaque formation and cholesterol content in the aorta. Although E5324 did not lower plasma cholesterol, atherosclerotic plaque formation in the aortic arch and thoracic aorta was reduced (by about 34% and 41%, respectively, at the high dose; P < 0.05). Cholesterol content in the aortic arch and thoracic aorta was also reduced (by about 59% and 62% at the high dose, respectively) compared with the control. These results suggest that E5324 acts directly on the arterial wall through ACAT inhibition, and prevents the progression of atherosclerosis in WHHL rabbits.

Analysis of Variance↗
PubMed1989

Comparative induction of drug-metabolizing enzymes by hypolipidaemic compounds.

1. The inducing effect of hypolipidaemic compounds containing arylcarboxylic structure (fenofibrate, bezafibrate, ciprofibrate) on drug-metabolizing enzymes was compared with that of other chemically different molecules (probucol, 1-benzylimidazole) in rat liver. 2. Hepatomegaly was closely associated to the decrease in triglycerides and cholesterol contents in plasma. 3. Lauric acid hydroxylation and hydratation of trans-stilbene oxide by the cytosolic epoxide hydrolase were markedly increased by the arylcarboxylic acids (fenofibrate, bezafibrate and ciprofibrate). The determination of the concentration in microsomal epoxide hydrolase by immunoassay revealed no change in the protein amount within the membrane; only the specific activity was enhanced by bezafibrate and 1-benzylimidazole, suggesting an activation process. 4. Bilirubin glucuronidation was increased by the arylcarboxylic structures and by 1-benzylimidazole; by contrast probucol decreased this activity.

Animals↗
PubMed2004

Inhibitory effects of multi-substituted benzylidenethiazolidine-2,4-diones on LDL oxidation.

Multi-substituted benzylidenethiazolidine-2,4-diones 3a-h were synthesized by Knoevenagel condensation of di- or tri-substituted 4-hydroxybenzaldehydes [or 1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone] 1 with thiazolidine-2,4-dione (2) and evaluated for antioxidant activities of Cu(2+)-induced oxidation of human low-density lipoproteins (LDL). Among compounds 3a-h, 3a was superior to probucol in LDL-antioxidant activities and found to be ninefold more active than probucol. Due to its potency, compound 3a was tested for complementary in vitro investigations, such as TBARS assay (IC(50) = 0.1 microM), lag time (240 min at 1.5 microM), relative electrophoretic mobility (REM) of ox-LDL (inhibition of 83% at 10 microM), fragmentation of apoB-100 (inhibition of 61% at 5 microM), and radical DPPH scavenging activity on copper-mediated LDL oxidation. In macrophage-mediated LDL oxidation, the TBARS formation was also inhibited by compound 3a.

Antioxidants↗
PubMed2006

Different inflammatory response and oxidative stress in neointimal hyperplasia after balloon angioplasty and stent implantation in cholesterol-fed rabbits.

Inflammatory responses appear to play an important role in the occurrence of restenosis following coronary intervention. However, the contribution of C-reactive protein (CRP) and oxidative stress to restenosis after balloon angioplasty and stent implantation remains unclear. The aim of this study was to examine this issue using hyperlipidemic rabbits. Rabbits were divided into two groups; they were fed with a 0.5% cholesterol diet and with a mixed 0.5% cholesterol and 0.5% probucol diet. Each group of rabbits underwent balloon injury and stent implantation in right and left iliac arteries, respectively. Eight weeks after the intervention, we examined luminal stenosis, neointimal hyperplasia, immunoreactivity for macrophage, CRP and oxidized phosphatidylcholine (oxPC), and also the expression of CRP mRNA. The degrees of neointimal hyperplasia and immunopositive areas (%) for macrophage, CRP, and oxPC in the neointima were significantly higher after stent implantation than after balloon injury, but CRP mRNA was undetectable in either artery. Anti-oxidant probucol reduced angiographic stenosis, neointimal hyperplasia, and macrophage- and oxPC-positive areas much more significantly after stenting. The results demonstrate that the inflammatory response to the development of neointimal hyperplasia differs after balloon injury and stent implantation and that CRP deposition and oxidative stress might be involved more significantly in neointimal development after stent implantation.

Angioplasty, Balloon↗
PubMed2003

NF-kappa B activation in endothelial cells treated with oxidized high-density lipoprotein.

We first determined whether oxidized high-density lipoprotein (ox-HDL) activates transcription factor nuclear factor-kappa B (NF-kappa B) in cultured human umbilical vein endothelial cells (HUVECs). Treatment for 7h with 100 microg/ml ox-HDL elicited a marked downregulation of I kappa B alpha and upregulation of the phosphorylated form of I kappa B alpha in HUVECs in a manner dependent on the dose of ox-HDL. Electrophoretic mobility shift assay in nuclear fraction from HUVECs showed translocation of NF-kappa B to the nucleus and binding of NF-kappa B to NF-kappa B consensus oligonucleotides during ox-HDL exposure for 7h, suggesting that ox-HDL brings about NF-kappa B activation in endothelial cells. To clarify the mechanism of NF-kappa B activation in HUVECs treated with ox-HDL, we investigated the effect of ox-HDL treatment on intracellular production of reactive oxygen species (ROS) in HUVECs. Ox-HDL induced a significant dose-dependent increase in ROS production during 4h incubation and this enhanced production of ROS was inhibited in the presence of probucol or diphenylene iodonium (DPI), an inhibitor of NADPH oxidase. In addition, pretreatment with probucol or DPI suppressed the phosphorylation and degradation of I kappa B alpha protein induced by ox-HDL, demonstrating that increased generation of ROS by ox-HDL may be associated with NF-kappa B activation. Pretreatment with antibody against oxidized low-density lipoprotein receptor-1 (LOX-1) significantly suppressed the ox-HDL-induced downregulation of I kappa B alpha, suggesting that LOX-1 mediates NF-kappa B activation in endothelial cells stimulated with ox-HDL. Taking all of the above findings together, ox-HDL activates NF-kappa B via binding to LOX-1 on the cell surface, followed by enhancement of intracellular ROS production in endothelial cells.

Blotting, Western↗
PubMed2000

Vitamin E supplementation increases the resistance of both LDL and HDL to oxidation and increases cholesteryl ester transfer activity.

There is increasing evidence that lipid peroxidation and oxidative modification of low density lipoprotein (LDL) is important in atherogenesis. Evidence that antioxidant therapy decreases mortality is, however, inconclusive. We have examined the effects of vitamin E on the susceptibility of LDL and high density lipoprotein (HDL) to oxidation, and on cholesteryl ester heteroexchange in an in vitro system using autologous serum lipoproteins. Vitamin E in doses of 200 and 400 mg/day were administered orally to 21 healthy volunteers (12 females and nine males) aged between 23 and 50 years, and to 16 healthy volunteers (eight females and eight males) aged between 22 and 51 years for 50 days, respectively. Fasting serum lipoproteins, susceptibility of lipoproteins to oxidation and cholesteryl ester transfer activity (CETA) were measured before and after vitamin E supplementation. Serum lipoprotein and lipid concentrations did not change significantly in either group. The LDL-conjugated diene (CD) lag phase during incubation with Cu(2+) was increased by 157% (110-232%) (median (interquartile range)) (P<0.05) on vitamin E (200 mg/day) and by 235% (185-259%) (P<0.0001) on 400 mg/day. The lag phases for LDL-lipid peroxide (LPO) generation were also significantly increased by 146% (122-192%) (P<0.005) and 177% (101-267%) (P<0.005), respectively. The HDL-CD lag phase also increased on both doses 140% (115-169%) (P<0.005) and 171% (122-192%) (P<0.005), as did the HDL-LPO lag phase by 123% (104-153%) (P<0.05) on 200 mg/day and 240% (97-360%) (P<0.005) on 400 mg daily. Cholesteryl ester transfer activity from HDL to very low and low density lipoproteins significantly increased from 12. 7+/-2.6 (mean+/-SEM) to 16+/-3.4 nmol/ml/h (P<0.05) on 200 mg/daily and 10.4+/-2.0 to 19.2+/-3.3 nmol/ml/h (P<0.005) on vitamin E, 400mg day. Thus, vitamin E (200 and 400mg daily) significantly decreased the susceptibility of LDL and HDL to oxidation in vitro. However, the increase in CETA resembled that reported with another antioxidant, probucol. Some evidence has suggested that increased CETA is potentially deleterious and it might therefore counteract beneficial effects of vitamin E or probucol on the susceptibility of lipoproteins to oxidation.

Adult↗
PubMed2000

Mode of action of sesame lignans in protecting low-density lipoprotein against oxidative damage in vitro.

We investigated the antioxidant properties of sesaminol, a major component of sesame oil, on the oxidative modification of human low-density lipoprotein (LDL) in vitro. Sesaminol inhibited the Cu2+-induced lipid peroxidation in LDL in a concentration-dependent manner with an IC50 36.0 +/- 10.0 nM. Sesaminol was a more effective scavenger than either alpha-tocopherol or probucol in reducing the peroxyl radicals derived from 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) in aqueous solution. In addition, as determined by the secondary products of lipid peroxidation identified by using immunochemical methods, sesaminol completely inhibited the formation of 4-hydroxy-nonenal (4-HNE)- and malondialdehyde (MDA)-adducts in a concentration-dependent manner. Probucol and alpha-tocopherol at the same concentration exhibited a lesser inhibitory effect. Our findings suggest that sesaminol is a potentially effective antioxidant that can protect LDL against the oxidation.

Antioxidants↗
PubMedDate not supplied

Effects of antihyperlipidemic drugs and diet plus exercise therapy in the treatment of patients with moderate hypercholesterolemia.

We compared the efficacy of two antihyperlipidemic drugs and the efficacy of diet plus exercise therapy in the treatment of patients with moderate hypercholesterolemia. The study included 48 patients with moderate hypercholesterolemia (serum total cholesterol [TC], 250 to 320 mg/dL). Patients were divided into three groups: group A--patients administered 10 mg/d of pravastatin; group B--patients administered 500 mg/d of probucol and 600 mg/d of pantethine; and group C--patients administered diet plus exercise therapy. The serum TC and serum high-density lipoprotein cholesterol (HDL-C) values were determined via enzymatic methods before initiation of each therapy and after 4 and 8 weeks of therapy. An atherogenic index (AI) was also calculated. The results indicated that TC showed a statistically significant decrease in all three groups at 4 and 8 weeks (P < 0.001 and P < 0.05, respectively); the HDL-C value did not change significantly in groups A and C, but it had a statistically significant decrease in group B at 4 and 8 weeks. The AI showed a statistically significant decrease in group A at 4 and 8 weeks of treatment and group C at 8 weeks; there were no significant changes in AI in group B. It may be concluded that as an antihyperlipidemic agent, pravastatin is more useful than probucol and that appropriate exercise and strict dietary management for 8 weeks achieve an efficacy close to that achieved by drug therapy.

Cholesterol, HDL↗
PubMed2002

DNA damage and the effect of antioxidants in streptozotocin-treated mice.

Streptozotocin (STZ) has drawn attention as a potential source of oxidative stress, which induces genotoxicity. We investigated the effects of STZ on DNA damage in the liver and kidney, as well as the protective effects of antioxidants, by using the alkaline single-cell gel electrophoresis assay, and by measuring the ratio of 8-hydroxy-2'-deoxyguanosine (8-OHdG) to dG. A single intraperitoneal injection of STZ (150 mg/kg) increased serum levels of glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and blood urea nitrogen (BUN), and also caused DNA damage in the liver and kidney, which recovered slowly with time. Antioxidants,(ascorbic acid, trolox and probucol) prevented the STZ-induced elevation of DNA damage in the liver and kidney and inhibited the increase in serum levels of AST, ALT and BUN. Thus ascorbic acid, trolox, and probucol protected the mice against STZ-induced DNA damage that might contribute to the development of hepatic or renal disease.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2004

Alpha-tocopherol preserves endothelial cell migration in the presence of cell-oxidized low-density lipoprotein by inhibiting changes in cell membrane fluidity.

OBJECTIVE: Endothelial cell (EC) migration is essential for healing areas of arterial injury and angioplasty sites. Iron or copper-oxidized low-density lipoprotein (oxLDL(Cu)) inhibits EC migration in vitro, but the effect of physiologically relevant monocyte/macrophage-oxidized LDL (oxLDL(cell)) is unknown. We postulated that oxLDL(cell) would inhibit EC migration and that this inhibition would be reversed by antioxidants. METHODS: The effect of oxLDL(Cu) and oxLDL(cell) on EC migration was studied by using a razor scrape assay, and migration was assessed after 24 hours. In addition, ECs were incubated with various antioxidants, including butylated hydroxytoluene (BHT), probucol, or alpha-tocopherol, for 1 hour prior to initiation of the scrape assay and application of oxLDL. RESULTS: Both oxLDL(Cu) and oxLDL(cell) inhibited migration. The antioxidants did not alter the antimigratory activity of oxLDL(Cu), but alpha-tocopherol preserved EC migration in the presence of oxLDL(cell). The lack of effect of BHT or probucol suggested that the effect of alpha-tocopherol resided not in its antioxidant activity but in its membrane-stabilizing properties. To test this theory, the effect of oxLDL and alpha-tocopherol on relative cell membrane fluidity was assessed by fluorescence recovery after photobleaching. Both oxLDL(Cu) and oxLDL(cell) increased relative membrane fluidity. Preincubation with alpha-tocopherol inhibited the increase in membrane fluidity of ECs incubated in oxLDL(cell) but not in oxLDL(Cu). CONCLUSIONS: These studies show that alpha-tocopherol preserves EC migration in oxLDL(cell) and hastens restoration of the endothelial monolayer after injury by inhibiting changes in membrane integrity caused by oxLDL. CLINICAL RELEVANCE: Recent studies find that vitamin E is not efficacious in the secondary prevention of cardiovascular events, perhaps because vitamin E does not efficiently block oxidation pathways known to be operative in atherosclerotic arteries. "Non-antioxidant" properties of vitamin E, however, could be important in the primary prevention of atherosclerosis and its complications. Our in vitro studies show that alpha-tocopherol can preserve endothelial migration in the presence of cell-oxidized LDL. This effect might improve the healing of endothelial injuries at sites of arterial repair or angioplasties, especially in lipid-laden arterial walls.

Animals↗
PubMed1997

Antioxidants inhibit the expression of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 induced by oxidized LDL on human umbilical vein endothelial cells.

The oxidative modification of low density lipoprotein (LDL) and the endothelial expression of adhesion molecules are key events in the pathogenesis of atherosclerosis. In this study we evaluated the effect of oxidized LDL on the expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin on human umbilical vein endothelial cells (HUVECs). The hypothesis that oxidized LDL functions as a prooxidant signal was also evaluated, by studying the effect of different radical-scavenging antioxidants on expression of adhesion molecules. LDL was oxidized by using Cu2+, HUVECs or phospholipase A2 (PLA2)/ soybean lipoxygenase (SLO), the degree of oxidation being measured as thiobarbituric acid-reactive substances (TBARS) and conjugated dienes (CD). Exposure of 200 micrograms/ml of native LDL to 1 microns Cu2+, HUVECs and to PLA2/ SLO resulted in four- to fivefold higher levels of TBARS and CD than in native LDL. Cu(2+)-(1 microM), HUVEC-, and PLA2/SLO-oxidized LDL caused a dose-dependent, significant increase of ICAM-1 and VCAM-1 (p < .01). The expression of E-selectin did not change. LDL oxidized with a 2.5 and 5 microM Cu2+ did not increase ICAM-1 and VCAM-1 significantly. Both the Cu(2+)- and HUVEC-oxidized LDL, subjected to dialysis and ultrafiltration, induced ICAM-1 and VCAM-1 expression. After incubation with the ultrafiltrate, the expression of ICAM-1 and VCAM-1 was not significantly different from that obtained with native LDL. LDL pretreated with different antioxidants (vitamin E and probucol) and subjected to oxidation by Cu2+ and HUVECs induced a significantly lower expression of ICAM-1 and VCAM-1 than nonloaded LDL (p < .01). The pretreatment of HUVECs with vitamin E and probucol significantly reduced the expression of VCAM-1 on HUVECs induced by oxidized LDL (p < .01); the effect on ICAM-1 was much less evident. In conclusion, oxidized LDL can induce the expression of different adhesion molecules on HUVECs; this induction can be prevented by pretreating either the LDL or the cells with radical-scavenging antioxidant.

Antioxidants↗
PubMed1991

Synthesis and biological activity of new HMG-CoA reductase inhibitors. 3. Lactones of 6-phenoxy-3,5-dihydroxyhexanoic acids.

A group of 43 optically active sodium carboxylates (11a-qq and the corresponding lactones 4 were prepared from respective phenols 8 according to Schemes I-III. Phenols 8 were synthesized from commercially available compounds according to Schemes IV-IX. A number of these HMG-CoA reductase inhibitors 11 exceeded mevinolin's activity in vitro (Tables II and III). Selected lactones 4 effectively inhibited hepatic "de novo" cholesterol synthesis in rats in vivo (Table IV). After po administration to rabbits, 4ff(11ff), 4hh, and notably 11jj reduced plasma cholesterol levels more potently than mevinolin (Table V). Whereas 4ff(11ff) displayed the slight superiority expected according to in vitro data, 4hh and 11jj were considerably more potent than expected. Each of these compounds had only moderate activity after po administration to dogs (Table VI). Compound di-11ii, a hybrid of the structural elements of probucol and HMG-CoA reductase inhibitors, after po administration to rats decreased serum lipoproteins and increased HDL/LDL ratio better than probucol (Table VII). HMG-CoA reductase inhibitor 11ll and phenolic building blocks 8, notably 8jj and 8kk, inhibited LDL oxidation in vitro (Table VIII). Chemical structure-activity relationships (Table IX) and the pharmacological profile of phenoxy-type inhibitors 11 diverged from those of known HMG-CoA reductase inhibitors.

Animals↗
PubMed1997

Beta-amyloid neurotoxicity in vitro: evidence of oxidative stress but not protection by antioxidants.

Recent data from several groups suggest that the primary mechanism of beta-amyloid neurotoxicity may be mediated by reactive oxygen species. To evaluate this hypothesis, we first compared the efficacy of antioxidant agents in preventing toxicity caused by oxidative insults (iron, hydrogen peroxide, and tert-butyl hydroperoxide) and beta-amyloid peptides in cultured rat hippocampal neurons. Tested antioxidants (propyl gallate, Trolox, probucol, and promethazine) generally provided significant protection against oxidative insults but not beta-amyloid peptides. Next, we examined whether beta-amyloid causes oxidative stress, by comparing levels of lipid peroxidation after exposure to either iron or beta-amyloid. In a cell-free system, iron but not beta-amyloid generated lipid peroxidation. In culture, both insults caused rapid increases in lipid peroxidation, with iron inducing higher levels at later time points. Pretreatment with the antioxidant probucol significantly reduced lipid peroxidation caused by both insults but only attenuated iron toxicity, suggesting that lipid peroxidation does not contribute directly to cell death induced by beta-amyloid. Finally, we observed that increasing basal levels of oxidative stress by pretreating cultures with subtoxic doses of iron significantly increased neuronal vulnerability to beta-amyloid. The ability of beta-amyloid to induce oxidative stress and the demonstration that oxidative stress potentiates beta-amyloid toxicity support the clinical use of antioxidants for AD. However, these data do not support the theory that the primary mechanism of beta-amyloid toxicity involves oxidative pathways, indicating a continued need to identify additional cellular responses to beta-amyloid that underlie its neurodegenerative actions.

Amyloid beta-Peptides↗