Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the ability of NAC to inhibit in vitro LDL oxidation, and the effects of the timing of NAC addition, repeated additions of NAC, and the presence of preoxidized LDL, on the oxidation reaction. NAC inhibited in vitro LDL oxidation induced by copper sulfate, 2,2'-azobis(2-amidinopropane) dihydrochloride, and UV light, and protected LDL against depletion of antioxidant vitamins. Glutathione was similarly effective against copper-mediated LDL oxidation. NAC's effectiveness was inversely related to the timing of its addition. Sequential NAC additions prolonged the lag phase more effectively than initial addition of the same total dose. NAC reduced CD formation during the oxidation of native LDL by oxidized LDL. NAC's effectiveness as an inhibitor of in vitro LDL oxidation is dependent on the temporal sequence of the oxidation reaction, sequential additions, and the presence of previously oxidized LDL.
Atherosclerosis 1998 Jun
PMID:Temporal and kinetic determinants of the inhibition of LDL oxidation by N-acetylcysteine (NAC). 969 Sep 15

The pineal hormone, melatonin, was recently found to be a potent free scavenger for hydroxyl and peroxyl radicals. Melatonin also inhibits neuronal and thymocyte damage due to oxidative stress. Atherosclerosis development is mediated by low-density lipoprotein (LDL) oxidation and the endocytosis of oxidized LDL by resident macrophages in the subendothelial vascular wall. Furthermore, the cytotoxic effect of oxidized LDL increases atherogenicity. The goal of this study was to compare the antioxidant activities of melatonin and vitamin E against in vitro LDL oxidation and their cytoprotective actions against oxidized LDL-induced endothelial cell toxicity. An attempt at loading LDL with melatonin by incubating human plasma with an ethanolic melatonin solution gave only low protection against Cu2+-induced LDL oxidation in comparison with vitamin E and gave no detectable incorporation of melatonin into LDL, measured by high-performance liquid chromatography (HPLC) coupled to UV detection. High concentrations of melatonin (10-100 microM) added to the oxidative medium induced a clear inhibition of Cu2+-induced LDL oxidation, characterized as an increase in the lag-phase duration of conjugated diene formation and decreases in the maximal rate of the propagation phase and in the maximal amount of conjugated diene formation. Determination of the median efficacious dose (ED50) of melatonin and vitamin E by their ability to increase lag-phase duration showed that melatonin was less active than vitamin E (ED50, 79 vs. 10 microM, respectively). Melatonin was also less active than vitamin E in limiting the formation of thiobarbituric acid-reactive substances (TBARS) and LDL fluorescence intensity increase in the medium during Cu2+-induced LDL oxidation. Cu2+-induced LDL oxidation in the presence of 100 microM melatonin produced oxidized LDLs that were less recognizable for the scavenger receptors of J774 macrophages than were untreated LDLs. Vitamin E, 10 microM, was more active than 100 microM melatonin in inhibiting LDL oxidation and the resulting lipoprotein alterations leading to binding internalization and degradation by the J774 macrophages. Vitamin E, 100 microM, inhibited the pursuit of the oxidation of oxidized LDL mediated by bovine aortic endothelial cells (BAECs) in a culture medium containing Cu2+, whereas 100 microM melatonin had no antioxidant effect. Melatonin, 100 microM, as well as 100 microM vitamin E inhibited intracellular TBARS formation during the incubation of BAECs with highly oxidized LDL but had no influence on the increase in glutathione (GSH) concentration during this lengthy exposure (16 h) of BAECs to highly oxidized LDL. During this period, the same dose of vitamin E but not of melatonin tended to limit the decrease in adenosine triphosphate (ATP) concentration. Vitamin E, 100 microM, did not significantly reduce cellular lactate dehydrogenase (LDH) release in the culture medium during the incubation of oxidized LDL with BAECs, whereas 100 microM melatonin dramatically increased this release. These data show that melatonin is less active than vitamin E in inhibiting in vitro LDL oxidation and does not inhibit the cytotoxicity of oxidized LDL toward cultured endothelial cells. The concentrations necessary to inhibit LDL oxidation are far beyond those found in human plasma (100 microM vs. 100 pM). Therefore our results indicate that the pineal hormone melatonin per se appears to have little antiatherogenic property in the in vitro oxidation of LDL and the cytoprotective action against the toxicity of oxidized LDL. Nevertheless, in vivo LDL oxidation takes place in the subendothelium of the artery wall, and nothing is known about the concentration of melatonin or its catabolites in this environment.
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PMID:A high concentration of melatonin inhibits in vitro LDL peroxidation but not oxidized LDL toxicity toward cultured endothelial cells. 978 26

Macrophage death, believed to be an important event in the pathogenesis of human atherosclerosis, can be induced by oxidised low-density lipoprotein (LDL) in vitro. Supplementation of the culture medium with 5 mM GSH significantly protected human monocyte-macrophages in vitro against the toxicity of copper-oxidised LDL. Oxidation products of LDL include the aldehyde 4-hydroxynonenal (HNE). We present evidence that conjugation of HNE by GSH contributes to this protection. In the absence of cells, HPLC analysis showed there were marked reductions in the levels of both pure HNE and HNE in copper-oxidised LDL in the presence of GSH. However, GSH did not reverse protein modification, as judged by agarose gel electrophoresis, nor did it influence the depletion of polyunsaturated fatty acids, which were assessed using gas chromatography. The possible implications for human atherosclerosis are discussed.
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PMID:Glutathione (GSH) and the toxicity of oxidised low-density lipoprotein to human monocyte-macrophages. 1019 69

Oxidation of low-density lipoprotein (LDL) has been recognized as playing an important role in the initiation and progression of atherosclerosis. We recently reported that S-allylcysteine (SAC), one of the major compounds in the aged garlic extract (AGE), inhibited LDL oxidation and minimized oxidized LDL-induced cell injury. In this study, the antioxidant effects of SAC were further determined using several in vitro assay systems. Pulmonary artery endothelial cells (PAECs) were preincubated with SAC at 37 degrees C and 5% CO2 for 24 hr, washed, and then exposed to 0.1 mg/ml oxidized LDL for 24 hr. Lactate dehydrogenase (LDH) release, as an index of membrane injury, and intracellular glutathione (GSH) level were determined. Oxidized LDL caused an increase of LDH release and depletion of GSH. Pretreatment with SAC prevented these changes. Peroxides were measured directly in 24-well plates using a fluorometric assay. SAC dose-dependently inhibited oxidized LDL-induced release of peroxides in PAEC. In a cell-free system, SAC was shown to scavenge hydrogen peroxide. Our data demonstrate that SAC can protect endothelial cells from oxidized LDL-induced injury by removing peroxides and preventing the intracellular GSH depletion and suggest that this compound may be useful for the prevention of atherosclerosis.
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PMID:S-allylcysteine attenuates oxidative stress in endothelial cells. 1021 31

Oxidation of low density lipoprotein (LDL) has been recognized as playing an important role in the initiation and progression of atherosclerosis. We recently reported that aged garlic extract (AGE) inhibited LDL oxidation and minimized oxidized LDL-induced cell injury. In this study, the antioxidant effects of AGE were further examined using bovine pulmonary artery endothelial cells (PAEC) and murine macrophages. Lactate dehydrogenase (LDH) release, as an index of membrane injury, and intracellular glutathione (GSH) levels were determined. Oxidized LDL (Ox-LDL) caused an increase of LDH release and depletion of GSH. Pretreatment with AGE prevented these changes. AGE exhibited an inhibition of Ox-LDL-induced peroxides in PAEC. AGE suppressed peroxides in murine Macrophage (J774 cells) dose-dependently. The J774 cells were also incubated with AGE, interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) and nitric oxide (NO) production was measured. AGE inhibited NO production in J774 cells. In a cell free system, AGE was shown to scavenge H2O2 dose-dependently. Our data demonstrate that AGE can protect the endothelial cells from oxidized LDL-induced injury by preventing depletion of intracellular GSH and by removing peroxides. AGE also reduces levels of NO and peroxides in macrophages. These data suggest that AGE is a useful protective agent against cytotoxicity associated with Ox-LDL and NO, and it may thus be useful for the prevention of atherosclerosis and cardiovascular diseases.
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PMID:Aged garlic extract attenuates intracellular oxidative stress. 1037 52

The dithiocarbamates are well known for their antioxidant properties and effects on cellular transcriptional events. For example, pyrrolidine dithiocarbamate (PDTC) is widely used as an inhibitor of nuclear factor kappa B (NFkappaB) and this, or related compounds may have therapeutic potential in inhibiting atherosclerosis. However, the precise molecular mechanisms through which PDTC could elicit antioxidant or cell signaling effects in a cellular setting remain unclear. Furthermore, the mechanisms for the effects of PDTC on NFkappaB are likely to involve inhibition of binding of the transcription factor to DNA rather than an effect on the activation process as first proposed. In relation to pharmacological applications of such compounds, little is known of their interaction with endothelial cells, the anticipated site of action for inhibition of vascular related diseases. Until recently, PDTC was generally classified as an antioxidant but evidence for pro-oxidant effects have been reported. In this study, we have addressed this issue in bovine aortic endothelial cells and identified two mechanisms through which PDTC can exert antioxidant effects. At low concentrations (0-25 microM), PDTC induces a concentration dependent increase in cellular GSH levels through the increased activity of gamma-glutamylcysteine synthetase. At higher concentrations, GSH oxidation and apoptotic cell death occur. Using 2,3 dimethoxy-1,4-napthoquinone (DMNQ) as an intracellular generator of superoxide radicals, we find PDTC (10 microM) protects against the cytotoxicity of this agent through a GSH-independent mechanism.
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PMID:Effects of pyrrolidine dithiocarbamate on endothelial cells: protection against oxidative stress. 1038 Nov 84

Allylamine (AA) is a cardiovascular toxin that causes lesions resembling atherosclerosis in several mammalian species. AA's toxic effects are thought to be exerted through its conversion to acrolein (AC), a potent electrophilic alkylating agent and atherogen. Semicarbazide sensitive amine oxidase (SSAO) catalyzes the oxidation of AA to AC. Glutathione S-transferases (GST) can catalyze the first step of detoxification of AC to mercapturic acid. Our previous studies suggest that the isozyme rGST8-8 is a principal defense against electrophilic stress exerted by alpha,beta-unsaturated carbonyls such as AC. In the present studies, we use cultured rat vascular smooth muscle cells (VSMC) to examine the relative roles of SSAO and rGST8-8 in the cytotoxic effects of the atherogens, AA and AC. Exposure derived AA-resistant cells (VSMC-AA) were 3.5-fold more resistant to AA when compared to VSMC and 1.8-fold more resistant to acrolein. SSAO activity was 2-fold higher in VSMC-AA than in VSMC. Consistent with the role of SSAO in biotransformation of AA, the SSAO inhibitor semicarbazide (SC; 100 microM) provided nearly complete protection from AA to both VSMC-AA and VSMC. As expected, SC did not affect the cytotoxicity of AC. Pretreatment with 100 microM sulfasalazine (SS), a GST inhibitor, potentiated AA and AC toxicity in both VSMC-AA and VSMC, indicating a protective role of GST. Catalytic efficiency (K(cat)/K(m)) of GSTs was higher toward 4-hydroxynonenal (4-HNE) (0.65 mM(-1) s(-1)) than toward 1-chloro-2, 4-dinitrobenzene (CDNB) (0.14 mM(-1) s(-1)) for VSMC. In VSMC-AA, K(cat)/K(m) was increased 4.1-fold toward CDNB (0.58 mM(-1) s(-1)) and 6-fold toward 4HNE (3.9 mM(-1) s(-1)) when compared to VSMC, indicating a preferential increase in VSMC-AA of GST isozymes which utilize alpha,beta-unsaturated carbonyls. Western blots confirmed induction of rGST8-8 in VSMC-AA. Expression of recombinant mGSTA4 (the mouse homolog of rGST8-8) in VSMC caused a 1.6-fold increase in resistance to AA and AC. This resistance was fully reversed by 50 microM SS. Our results demonstrate that GSTs are an important defense against electrophilic atherogens and that isozymes with high activity toward alpha,beta-unsaturated carbonyls are particularly important in the vascular wall.
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PMID:Role of glutathione S-transferase 8-8 in allylamine resistance of vascular smooth muscle cells in vitro. 1040 32

Dietary oxysterols can reach the circulation and this may contribute to atherosclerosis, where lipid oxidation is thought to be important. There is also evidence that, in rats, peroxidized lipids are absorbed and transported into lymph [Aw TY, Williams MW, Gray L. Absorption and lymphatic transport of peroxidized lipids by rat small intestine in vivo: role of mucosal GSH. Am J Physiol 1992; 262: G99-G106], although the method used to detect lipid peroxides lacked specificity. We tested whether intragastric administration of vegetable oils containing triglyceride hydroperoxides (TG-OOH) to rats resulted in detectable lipid hydroperoxides in mesenteric lymph. Using sensitive HPLC with postcolumn chemiluminescence detection, we were unable to detect hydroperoxides of triglycerides, cholesterylesters or phospholipids during the course of lipid absorption, and lymph levels of ascorbate, urate, alpha-tocopherol and ubiquinol-9 did not change significantly. By contrast, we observed a striking reducing activity judged by the efficient reduction of administered ubiquinones-9 and -10 to the corresponding ubiquinols. Exposure of rat lymph and isolated chylomicrons to aqueous peroxyl radicals revealed patterns of antioxidant consumption and lipid hydroperoxide formation similar to those described previously for human extravascular fluids and isolated lipoproteins, respectively. In particular, rates of TG-OOH formation in lymph and chylomicrons were very low to undetectable as long as ascorbate and/or ubiquinols were present, but subsequently proceeded in a chain reaction despite the presence of alpha-tocopherol. These studies demonstrate that rat intestine and mesenteric lymph possess efficient antioxidant defenses against preformed lipid hydroperoxides and (peroxyl) radical mediated lipid oxidation. We conclude that dietary lipid hydroperoxides or postprandial oxidation of lipids are not likely to contribute to these particular forms of oxidized lipids in circulation and aortic tissue.
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PMID:Antioxidant defenses in rat intestine and mesenteric lymph. 1049 10

Thanks to progress in zinc research, it is now possible to describe in more detail how zinc ions (Zn++) and nitrogen monoxide (NO), together with glutathione (GSH) and its oxidized form, GSSG, help to regulate immune responses to antigens. NO appears to be able to liberate Zn++ from metallothionein (MT), an intracellular storage molecule for metal ions such as zinc (Zn++) and copper (Cu++). Both Zn++ and Cu++ show a concentration-dependent inactivation of a protease essential for the proliferation of the AIDS virus HIV-1, while zinc can help prevent diabetes complications through its intracellular activation of the enzyme sorbitol dehydrogenase (SDH). A Zn++ deficiency can lead to a premature transition from efficient Th1-dependent cellular antiviral immune functions to Th2-dependent humoral immune functions. Deficiencies of Zn++, NO and/or GSH shift the Th1/Th2 balance towards Th2, as do deficiencies of any of the essential nutrients (ENs) - a group that includes methionine, cysteine, arginine, vitamins A, B, C and E, zinc and selenium (Se) - because these are necessary for the synthesis and maintenance of sufficient amounts of GSH, MT and NO. Via the Th1/Th2 balance, Zn++, NO, MT and GSH collectively determine the progress and outcome of many diseases. Disregulation of the Th1/Th2 balance is responsible for autoimmune disorders such as diabetes mellitus. Under Th2, levels of interleukin-4 (II-4), II-6, II-10, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) are raised, while levels of II-2, Zn++, NO and other substances are lowered. This makes things easier for viruses like HIV-1 which multiply in Th2 cells but rarely, if ever, in Th1 cells. AIDS viruses (HIVs) enter immune cells with the aid of the CD4 cell surface receptor in combination with a number of co-receptors which include CCR3, CCR5 and CXCR4. Remarkably, the cell surface receptor for LTB4 (BLTR) also seems to act as a co-receptor for CD4, which helps HIVs to infect immune cells. The Th2 cytokine II-4 increases the number of CXCR4 and BLTR co-receptors, as a result of which, under Th2, the HIV strains that infect immune cells are precisely those that are best able to accelerate the AIDS disease process. The II-4 released under Th2 therefore not only promotes the production of more HIVs and the rate at which they infect immune cells, it also stimulates selection for the more virulent strains. Zn++ inhibit LTB4 production and numbers of LTB4 receptors (BLTRs) in a concentration-dependent way. Zn++ help cells to keep their LTB4 'doors' shut against the more virulent strains of HIV. Moreover, a sufficiency of Zn++ and NO prevents a shift of the Th1/Th2 balance towards Th2 and thereby slows the proliferation of HIV, which it also does by inactivating the HIV protease. Research makes it look likely that deficiencies of ENs such as zinc promote the proliferation of Th2 cells at the expense of Th1 cells. Zinc deficiency also promotes cancer. Under the influence of Th1 cells, zinc inhibits the growth of tumours by activating the endogenous tumour-suppressor endostatin, which inhibits angiogenesis. The modern Western diet, with its excess of refined products such as sugar, alcohol and fats, often contains, per calorie, a deficiency of ENs such as zinc, selenium and vitamins A, B, C and E, which results in disturbed immune functions, a shifted Th1/Th2 balance, chronic (viral) infections, obesity, atherosclerosis, autoimmunity, allergies and cancer. In view of this, an optimization of dietary composition would seem to give the best chance of beating (viral) epidemics and common (chronic) diseases at a realistic price.
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PMID:Modern diets and diseases: NO-zinc balance. Under Th1, zinc and nitrogen monoxide (NO) collectively protect against viruses, AIDS, autoimmunity, diabetes, allergies, asthma, infectious diseases, atherosclerosis and cancer. 1049 17

Hypercholesterolemia is a primary risk factor for atherosclerosis, coronary artery disease, and myocardial infarction. We subjected low density lipoprotein receptor-deficient (LDLr -/-) and control (wild-type) mice to 30 minutes of myocardial ischemia and 120 minutes of reperfusion. Myocardial infarction per area at risk (AAR) was noted under baseline conditions to be significantly (P<0.05) smaller in the LDLr -/- mice compared with wild-type mice (24.7+/-3. 2% and 38.8+/-4.3% of AAR, respectively). Subsequently, mice were fed a high-cholesterol diet (HCD) for 2 or 12 weeks, which resulted in significant increases in serum cholesterol levels in both LDLr -/- and wild-type groups. After 2 weeks of the HCD, the LDLr -/- mice demonstrated a significant elevation (P<0.01) in myocardial necrosis per AAR (50.2+/-5.36% of AAR) compared with the normal-diet LDLr -/- group, whereas the short-term HCD-fed wild-type mice demonstrated no significant difference from baseline. In contrast, wild-type mice fed the HCD for 12 weeks revealed a significant (P<0. 05) decrease in necrosis per AAR, which was 22.5+/-3.2% of the AAR in comparison with that in the normal-diet wild-type mice (38.8+/-4. 3% of AAR). LDLr -/- mice on the same long-term HCD showed a similar significantly (P<0.05) decreased infarct size, which was 13.2+/-4.0% of the AAR. In additional experiments, we determined that myocardial tissue total glutathione (GSH) levels were reduced after 2 weeks of the HCD and were significantly increased after 12 weeks of the HCD in the LDLr -/- mouse heart. These data suggest that short-term cholesterol feeding renders the myocardium of LDLr -/- mice more susceptible to ischemia-reperfusion injury, whereas more long-term hypercholesterolemia confers cardioprotection in the LDLr -/- mouse heart.
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PMID:Effects of hypercholesterolemia on myocardial ischemia-reperfusion injury in LDL receptor-deficient mice. 1055 25


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