Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear factor-kappa B (NF-kappa B)/Rel transcription factors may be involved in atherosclerosis, as is suggested by the presence of activated NF-kappa B in human atherosclerotic lesions. The aim of the present study was to investigate the effects of oxidized LDL (oxLDL) on the NF-kappa B system in human THP-1 monocytic cells as well as adherent monocytes. Our results demonstrate that short-term incubation of these cells with oxLDL activated p50/p65 containing NF-kappa B dimers and induced the expression of the target gene IL-8. This activation of NF-kappa B was inhibited by the antioxidant and H2O2 scavenger pyrrolidine dithiocarbamate and the proteasome inhibitor PSI. The oxLDL-induced NF-kappa B activation was accompanied by an initial depletion of I kappa B-alpha followed by a slight transient increase in the level of this inhibitor protein. In contrast, long-term treatment with oxLDL prevented the lipopolysaccharide-induced depletion of I kappa B-alpha, accompanied by an inhibition of both NF-kappa B activation and the expression of tumor necrosis factor-alpha and interleukin-1 beta genes. These observations provide additional evidence that oxLDL is a potent modulator of gene expression and suggest that (dys)regulation of NF-kappa B/Rel is likely to play an important role in atherogenesis.
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PMID:Dysregulation of monocytic nuclear factor-kappa B by oxidized low-density lipoprotein. 935 52

Serum amyloid A (SAA) is a plasma protein that is associated with many inflammatory diseases including amyloidosis, arthritis, and atherosclerosis. SAA level is significantly increased during inflammatory condition, and such abnormal expression of this protein is linked to the pathogenesis of the above-mentioned diseases. A promoter element, designated as SAA-activating sequence (SAS), located between -280 and -226 has been implicated in the induction mechanism and a nuclear factor, SAS-binding factor (SAF), has been shown to bind to this region. In this report, using a cloned SAF gene in transient transfection assay, we provide evidence that SAF potentiates SAA gene expression through SAS element. Furthermore, we show that during lipopolysaccharide-mediated induction of SAF, heteromeric complex with transcription factor Sp1 is formed. Transfection assays using both transcription factor genes have demonstrated that SAF-Sp1 heteromer is a highly potent transactivator of SAA expression.
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PMID:Induction of serum amyloid A (SAA) gene by SAA-activating sequence-binding factor (SAF) in monocyte/macrophage cells. Evidence for a functional synergy between SAF and Sp1. 936 Sep 66

A moderate elevation of plasma homocysteine is a risk factor for atherosclerosis and arterial and veinous thrombosis. However, the mechanisms leading to vascular disorders are poorly understood because studies that have investigated the potential atherothrombogenicity of hyperhomocysteinemia in vivo are scarce. Using a rat model, we were the first to show that dietary folic acid deficiency, a major cause of basal hyperhomocysteinemia, is associated with enhanced macrophage-derived tissue factor and platelet activities. We proposed that an homocysteine-induced oxidative stress may account for this hypercoagulable state. To determine the true thrombogenicity of moderate hyperhomocysteinemia and better understand its etiology, we have carried out an acute methionine load in control and folate-deficient animals. When rats were fed the control diet, a transient fourfold increase in plasma homocysteine levels was observed 2 h after the methionine administration. As with prolonged dietary folic acid deficiency, this methionine load potentiated the platelet aggregation in response to thrombin and ADP as well as the thrombin-induced thromboxane synthesis. It also stimulated the basal and lipopolysaccharide-induced tissue factor activity of peritoneal macrophages. These prothrombotic effects were associated with an increased lipid peroxidation characterized by an elevation of plasma conjugated dienes, lipid hydroperoxides, and thiobarbituric acid-reactive substances. When rats were fed a folic acid-deficient diet, the methionine load did not cause any further increase in plasma homocysteine concentration, platelet activation, macrophage tissue factor-dependent coagulation, or lipoperoxidation. Altogether, our data showed that the prethrombotic state due to both the altered remethylation and transsulfuration pathways resulted from the moderate elevation of circulating homocysteine. We conclude that moderate hyperhomocysteinemia plays a role in the development of a thrombogenic state that might be mediated by the occurrence of oxidative stress.
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PMID:Acute methionine load-induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats. 936 51

In patients with diabetic renal failure, attention must be paid to the prevention of atherosclerosis as well as the preservation of renal function. Insulin resistance is one of the important risk-factors of atherosclerosis and the involvement of tumor necrosis factor-alpha (TNF-alpha) has been shown in the pathogenesis of insulin resistance in some diseases. A low-protein diet (LPD) is recommended for patients with advanced renal disease, but a large proportion of the total caloric intake is supplied from carbohydrates and fat in LPD. Therefore, we designed a study to determine: (1) the effect of TNF-alpha on insulin sensitivity, and (2) the effect of LPD on the TNF-alpha response and the risk factors of atherosclerosis, such as insulin sensitivity and lipid metabolism, in patients with diabetic renal failure. Insulin sensitivity was measured by an euglycemic hyperinsulinemic clamp technique and serum TNF-alpha level and in vitro release of TNF-alpha from peripheral blood mononuclear cells (PBMCs) was measured in patients with diabetic renal failure. A significant negative correlation was observed between lipopolysaccharide-stimulated TNF-alpha release from PBMCs and insulin sensitivity (r = -0.58, p < 0.05). Secondly, risk factors of atherosclerosis were measured before and two weeks after the introduction of LPD in patients with diabetic renal failure. LPD did not have any significant effect on insulin sensitivity, the production of TNF-alpha by PBMCs, lipid metabolism and glucose metabolism. These results indicate that: (1) TNF-alpha derived from PBMCs might affect insulin sensitivity in patients with diabetic renal failure, and (2) LPD does not have any significant effect on the risk factors of atherosclerosis.
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PMID:[Role of tumor necrosis factor-alpha in insulin sensitivity and effect of low protein diet on the TNF-alpha response in patients with diabetic renal failure]. 939 42

During vascular injury, such as observed in atherosclerosis, restenosis, vasculitides, transplantation, or sepsis, vascular smooth muscle cells (SMC) can be exposed to platelets or platelet products. Under these conditions proliferation or cytokine production of SMC stimulated by platelets or platelet products may contribute to regulation of vascular pathogenesis. Thus, we investigated interleukin-6 (IL-6) and IL-8 production as well as proliferation of SMC in response to platelets or platelet lysates. Platelets not already preactivated by thrombin induced IL-6 (10- to 50-fold) or IL-8 production of unstimulated SMC in a cell number dependent fashion. Preactivation of platelets with thrombin potently increased the platelet-mediated IL-6 (50- to 1,000-fold) and IL-8 production of SMC. Hirudin specifically inhibited the activation of platelets with thrombin. Isolated platelets cultured in the absence of SMC did not contain detectable IL-6 or IL-8. Prestimulation (4 hours) of SMC with pathophysiologically relevant substances (lipopolysaccharide [LPS], tumor necrosis factor-alpha [TNF-alpha], or IL-1alpha) further increased the platelet-induced cytokine production. The platelet-derived SMC stimulatory activity was IL-1, since IL-1 receptor antagonist (IL-1-Ra) inhibited the platelet-induced cytokine production of SMC. Anti-platelet-derived growth factor (PDGF)-antibody did not further reduce this activity. Thrombin itself stimulated expression of IL-6 and IL-8 to some degree and induced IL-6 production of SMC synergistically with IL-1. Platelets also induced proliferation of SMC, however, anti-PDGF antibodies, rather than IL-1-Ra blocked this response. These data show that platelet-derived IL-1 stimulates cytokine production of vascular smooth muscle cells, indicating that platelet-derived IL-1 may contribute to regulation of local pathogenesis in the vessel wall by activation of the cytokine regulatory network.
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PMID:Platelet-derived interleukin-1 induces cytokine production, but not proliferation of human vascular smooth muscle cells. 941 77

Increased plasma levels of homocysteine are an independent risk factor for atherothrombosis. While the endothelial cytotoxicity of homocysteine has been attributed to oxidative stress associated with the reactivity of the thiol group, the oxidative effect of homocysteine on vascular smooth-muscle cells has not been investigated. Recent evidence suggests that expression of inducible nitric oxide synthase (iNOS), or Nos2 gene product, in vascular smooth-muscle cells may, in part, promote atherosclerosis by increasing local oxidative stress. We therefore hypothesized that homocysteine contributes to atherosclerosis by affecting cytokine-induced production of nitric oxide (NO) by vascular smooth-muscle cells. Confluent rat aortic smooth-muscle cells were exposed to a range of concentrations of homocysteine for 4 hr, then were treated with interferon-gamma, interleukin-1 beta, and lipopolysaccharide to induce iNOS. Media NOx content (nitrite plus S-nitrosothiol) was measured over 24 hr using the Saville reaction. As compared to controls, 5, 50, and 500 microM homocysteine produced a dose-dependent increase in media NOx content, an effect that was primarily a consequence of increased S-nitrosothiol production. iNOS enzyme activity and iNOS protein levels were increased significantly in the homocysteine-treated cells as compared with controls. Northern analysis showed that homocysteine treatment increased steady-state Nos2 mRNA levels by 61% at 6 hr as compared with controls, an effect that was not caused by changes in message stability. By electrophoretic mobility shift assay, homocysteine activated NF-kappa B and also potentiated cytokine activation of NF-kappa B. These data demonstrate that exposure of vascular smooth-muscle cells to pathophysiologically relevant concentrations of homocysteine prior to cytokine stimulation leads both to an increase in NO production and to an NF-kappa B-mediated increase in Nos2 transcription. Upregulation of Nos2 may contribute to the inflammatory response that characterizes early atherogenesis and may, in part, account for the adverse vascular effects of hyperhomocysteinemia.
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PMID:Homocysteine-induced nitric oxide production in vascular smooth-muscle cells by NF-kappa B-dependent transcriptional activation of Nos2. 946 80

A major feature of macrophage metabolism is its capacity to produce and export cholesterol. Several reports have shown that the manipulation of lymphocyte cholesterol content elicits important changes in lymphocyte proliferation. These findings lead to an inquiry as to whether macrophage-derived cholesterol released into the lymphocyte surroundings may be transferred to the latter thus affecting lymphocyte function. In this study, cholesterol transfer from macrophages to lymphocytes was examined in vitro using rat cells in culture. The findings indicate that there may be a significant transfer of cholesterol from [4-14C]cholesterol labeled resident peritoneal macrophages to mesenteric lymph node resting lymphocytes (up to 173.9 +/- 2.7 pmol/10(7) lymphocytes/10(7) macrophages when co-cultivated for 48 h), in a lipoprotein-dependent manner. This represents the mass transfer of ca. 17 nmoles of cholesterol molecules per 10(7) lymphocytes from 10(7) macrophages (calculated on the basis of specific radioactivity incorporated into macrophages after the pre-labelling period), which suggests that macrophages are capable of replacing the whole lymphocyte cholesterol pool every 21 h. Moreover, an 111%-increase in the total cholesterol content of lymphocytes was found after co-cultivation with macrophages for 48 h. When compared to peritoneal cells, monocytes/macrophages obtained from circulating blood leukocytes presented a much higher cholesterol transfer capacity to lymphocytes (3.06 +/- 0.10 nmol/10(7) lymphocytes/10(7) macrophages co-cultivated for 24 h). Interestingly, inflammatory macrophages dramatically reduced their cholesterol transfer ability (by up to 91%, as compared to resident macrophages). Cholesterol transfer may involve a humoral influence, since it is not only observed when cells are co-cultivated in a single-well chamber system (cells in direct contact), but also in a two-compartment system (where cells can communicate but not by direct contact). Co-cultivation with macrophages decreased the basal incorporation of [2-14C]thymidine into lymphocyte DNA and the addition of cholesterol to lymphocyte culture media also impaired the lymphocyte proliferative response to the mitogens concanavalin A (Con A) and bacterial lipopolysaccharide (LPS). The above results suggest that macrophages may transfer cholesterol to lymphocytes (from both lymph nodes and blood), thus regulating lymphocyte function by raising the intracellular cholesterol content and suppressing lymphocyte proliferative activity. If this is so, a modulatory role for the transfer of cholesterol in both physiological (e.g. immune response) and pathological conditions (e.g. atherosclerosis) may be postulated. This hypothesis is currently under investigation in our laboratory.
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PMID:Transfer of cholesterol from macrophages to lymphocytes in culture. 953 May 17

Dietary long-chain fatty acids (FA) may influence pathological processes involving endothelial activation, including inflammation and atherosclerosis. We have previously shown that the n-3 FA docosahexaenoate (DHA) inhibits endothelial activation in the range of nutritionally achievable plasma concentrations. The present study assessed structural determinants for this effect. Saturated, monounsaturated, and n-6 and n-3 polyunsaturated FA were incubated with cultured endothelial cells for 24-72 h alone, and then in the presence of interleukin-1, tumor necrosis factor, or bacterial lipopolysaccharide for an additional 24 h before assessing the expression of the vascular cell adhesion molecule-1 (VCAM-1) or other products of endothelial activation. No FA tested per se elicited endothelial activation. While saturated FA did not inhibit cytokine-induced expression of adhesion molecules, a progressively increasing inhibitory activity was observed, for the same chain length, with an increase in double bonds. Comparison of FA with the same length and number of unsaturation and only differing for the double bond position or for the cis/trans configuration indicated no difference in inhibitory potency, indicating no effect of the double bond position or configuration. As judged by Northern analysis, these latter FA also inhibited VCAM-1 messenger RNA steady state levels to the same extent, indicating a pre-translational site of action attributable to the single double bond. Thus the double bond is the minimum necessary and sufficient requirement for FA inhibition of endothelial activation. These properties are likely relevant to the anti-atherogenic and anti-inflammatory properties ascribed to n-3 FA, which are able to accommodate the highest number of double bonds in a fatty acid of given chain length.
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PMID:Structural requirements for inhibition of cytokine-induced endothelial activation by unsaturated fatty acids. 961 Jul 74

Inducible nitric oxide synthase (iNOS) has recently been shown to be present in human atherosclerotic lesions and to promote the formation of deleterious peroxynitrite. Allicin and ajoene are discussed as active compounds with regard to the beneficial effects of garlic in atherosclerosis. The aim of this study was to investigate the effect of allicin and ajoene on the iNOS system in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Ajoene (IC50 2.5-5 microM) and allicin (IC50 15-20 microM) dose dependently reduced nitrite accumulation, a parameter for NO synthesis, in supernatants of LPS-stimulated (1 microg/ml, 20 h) macrophages. Accordingly, reduced iNOS enzyme activities were measured by conversion of L-[3H]arginine to L-[3H]citrulline in homogenates of LPS-activated cells treated with ajoene or allicin. None of these compounds, however, showed a direct effect on the catalytic-activity of iNOS. Consequently, iNOS protein and mRNA expression in ajoene (10 microM) or allicin (50 microM) treated cells were evaluated by Western blot and Northern blot analysis, respectively. Markedly reduced iNOS protein as well as mRNA levels were demonstrated. These observations indicate that allicin and ajoene inhibit the expression of iNOS in activated macrophages. The possible link of this effect to the beneficial features attributed to garlic is discussed.
Atherosclerosis 1998 Aug
PMID:Effect of allicin and ajoene, two compounds of garlic, on inducible nitric oxide synthase. 971 40

This paper evaluates the current information on the relationship between oral disease (specifically periodontitis) and atherosclerosis/coronary heart disease (CHD) to determine whether the information is sufficient to conclude that periodontitis is a risk factor for atherosclerosis/CHD. As background for this evaluation, the term "risk factor" is defined, and the 3 criteria used to establish exposures as risk factors are reviewed. In addition, epidemiologic criteria for defining an exposure as causal are presented. The available evidence then is evaluated according to the criteria for causality, which are extensions of the criteria for establishing a risk factor. This review is done in the context of the relationship between atherosclerosis/CHD and inflammation. A number of findings are briefly reviewed that link inflammation and atherosclerosis/CHD, such as: 1) prior flu-like symptoms were more common in cases of myocardial infarction than in concurrently sampled controls; 2) high levels of cytomegalovirus antibody titers were associated with elevated carotid intimal-medial wall thickness 18 years later; 3) prior infection with cytomegalovirus was a strong independent risk factor for restenosis after coronary atherectomy; 4) dental infections were more common in cases of cerebral infarction compared to community controls matched on age and sex; and 5) the gingival index was significantly correlated with fibrinogen and white cell counts in periodontal patients and controls, adjusted for age, smoking, and socioeconomic status. Three case-control studies and 5 longitudinal studies investigating the relationship between dental conditions and atherosclerosis/CHD are reviewed in terms of strength of associations, consistency of associations, specificity. of associations, time sequence between exposure and outcome, and degree of exposure and outcome. Related to the last criterion, new findings are presented which indicate that the extent of the periodontal infection, a measure reflecting microbial burden, also is related to onset of new CHD events. Our previously published model describing the potential biological mechanisms underlying the associations found is reviewed. This model places the associations into a context of an intrinsic or acquired hyperinflammatory monocyte trait that results in a more intense inflammatory response to lipopolysaccharide (LPS) challenges, such as periodontal infections. This hyperinflammatory response may promote atheroma formation and thromboembolic events. finally, new findings from ongoing animal studies are presented, indicating that high fat diets in atherosclerotic-susceptible mice induce greater inflammatory responses to Porphyromonas gingivalis challenges. We conclude that the available evidence does allow an interpretation of periodontitis being a risk factor for atherosclerosis/CHD. This conclusion, however. is made with some qualifications. While the associations found across a wide variety of subjects are remarkably consistent, for the most part they are represented by incidence odds ratios around 2.0. While this level of association would result in oral conditions contributing to a large number of CHD cases, it is possible that associations of this magnitude are due to bias in the study designs. In addition, some studies report that periodontitis is associated with all-cause mortality and low birth weight infants. These multiple associations detract from the credibility of periodontitis as a risk factor, as specificity of association is more often related to causality. However, all-cause mortality may largely be driven by mortality from cardiovascular events: and some exposures, such as smoking. are indeed risk factors for multiple conditions. On the other hand, current findings regarding the associations between oral conditions and atherosclerosis/CHD imply that the criteria for causality may be met in the not-too-distant future.
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PMID:Periodontitis: a risk factor for coronary heart disease? 972 97


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