Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

So-called coplanar polychlorinated biphenyls (PCBs), as well as other environmental contaminants that are aryl hydrocarbon receptor (AhR) agonists, may compromise the normal functions of vascular endothelial cells by activating oxidative stress-sensitive signaling pathways and subsequent proinflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. To test this hypothesis, porcine endothelial cells were exposed to PCB 153 and to three coplanar PCBs (PCB 77, PCB 126, or PCB 169). In contrast to PCB 153, which is not a ligand for the Ah receptor (AhR), all coplanar PCBs disrupted endothelial barrier function. All coplanar PCBs increased expression of the CYP1A1 gene, oxidative stress (DCF fluorescence), and the DNA-binding activity of nuclear factor kappaB (NF-kappaB). PCB-induced oxidative stress was concentration-dependent, with PCB 126 exhibiting a maximal response at the lowest concentration (0.5 microM) tested. The increase in NF-kappaB-dependent transcriptional activity was confirmed in endothelial cells by a luciferase reporter gene assay. In contrast to PCB 153, coplanar PCBs that are AhR ligands increased endothelial production of interleukin-6. At 3.4 microM, expression of the adhesion molecule VCAM-1 was most sensitive to PCB 77 and 169. We also provide in vivo evidence, suggesting that binding to the AhR is critical for the proinflammatory properties of PCBs. Twenty hours after a single administration of PCB 77, VCAM-1 expression was increased only in wild-type mice, while mice lacking the AhR gene showed no increased staining for VCAM-1. These data provide evidence that coplanar PCBs, agonists for the AhR, and inducers of cytochrome P450 1A1, produce oxidative stress and an inflammatory response in vascular endothelial cells. An intact AhR may be necessary for the observed PCB-induced responses. These findings suggest that activation of the AhR can be an underlying mechanism of atherosclerosis mediated by certain environmental contaminants.
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PMID:Proinflammatory properties of coplanar PCBs: in vitro and in vivo evidence. 1207 26

Cardiovascular pathology is the major cause of death in uraemia. There is evidence that a chronic inflammation with activation of C-reactive protein, interleukin-6, tumour necrosis factor-alpha and other cytokines is associated with vascular pathology, both in the general population and in dialysis patients. The cardiovascular system, and particularly the vascular wall, is the main target of the inflammatory process. Inflammation of the coronary arteries could be involved in the development of atherosclerosis and its related clinical syndromes. In the uraemic state, an increased production of pro-inflammatory cytokines may trigger the onset and progression of atherosclerosis and favour the subsequent complications, such as plaque fissuration and rupture. However, inflammatory cytokines also have a depressant action on the myocardium, thus inducing myocardial dysfunction. Together, these conditions may ultimately enhance the risk of myocardial infarction and death. From this standpoint, cardiovascular disease should also be investigated with the traditional biochemical inflammation markers and the evaluation of the circulating cytokine level, although new reliable markers could provide further diagnostic help. New therapeutic approaches should also be considered.
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PMID:Cardiac effects of chronic inflammation in dialysis patients. 1214 71

Inflammation is thought to play a central role in the aetiology and outcome of atherosclerosis. C-reactive protein (CRP) is a prominent product of the inflammatory response syndrome and a marker of overall and cardiovascular death in the general population and in dialysis patients. CRP is 5- to 10-fold higher in haemodialysis patients than in healthy controls and clearly is multifactorial in origin. A number of endogenous factors have been identified in vitro [angiotensin II, lipopolysacharide, modified low-density lipoprotein (LDL), advanced glycation end-products, homocysteine, viral infections] which all are able to trigger a nuclear factor (NF)-kappaB-mediated inflammatory, interleukin-6-driven, response via the generation of oxygen free radicals (oxidative stress). In addition, exogenous factors (dialysate endotoxin, vascular access, cuprophane dialyser material) have been identified in clinical studies which are also responsible, at least in part, for high serum CRP levels. Some of these factors function by themselves as non-traditional cardiovascular risk factors. Whether CRP is simply a marker of cardiovascular disease and mortality or whether it is in the causal pathway of the disease remains an open question. Recent data are in favour of a direct involvement in the pathogenesis of disease, since binding of CRP to degraded LDL enhances complement activation and induces the expression of tissue factor.
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PMID:C-reactive protein a marker for all-cause and cardiovascular mortality in haemodialysis patients. 1254 10

Flavonoids and related polyphenolics with antioxidant and anti-inflammatory activities may play a role in the prevention of cardiovascular disease by decreasing oxidative stress and inflammation. We wished to determine the effects of cocoa extract supplementation on markers of oxidative stress and inflammation. Healthy subjects (n = 25) were studied at baseline, after cocoa supplementation (36.9 g of dark chocolate bar and 30.95 g of cocoa powder drink) for 6 wk and after a 6-wk washout period. Fasting blood and early morning urine were collected at the three time points. Two indices of flavonoid intake, total phenols and oxygen radical absorbance capacity of plasma, were measured after an overnight fast. Neither was affected by supplementation. Measures of oxidative stress included copper-catalyzed LDL oxidation kinetics and urinary F(2) isoprostanes. LDL oxidizability was lower after chocolate supplementation as evidenced by a longer lag time (P < 0.05) of conjugated diene formation (101.0 +/- 20.7 min) compared with baseline (91.3 +/- 18.0 min) and washout (96.4 +/- 7.5 min) phases. There was no effect of chocolate on urinary F(2) isoprostane levels or on markers of inflammation including the whole-blood cytokines, interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha, high sensitivity C-reactive protein and P-selectin. In conclusion, cocoa products supplementation in humans affects LDL oxidizability, but not urinary F(2) isoprostanes or markers of inflammation.
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PMID:Cocoa products decrease low density lipoprotein oxidative susceptibility but do not affect biomarkers of inflammation in humans. 1246 4

Current research suggests that insulin resistance is associated with endothelial dysfunction, which is considered an early but significant step in the pathogenesis of atherosclerosis. Both insulin resistance and endothelial dysfunction appear to precede the development of overt hyperglycemia in patients with type 2 diabetes. Therefore, in patients with diabetes or insulin resistance, endothelial dysfunction may be a critical early target for preventing atherosclerosis and cardiovascular disease. Insulin-sensitizing agents--specifically, thiazolidinediones (TZDs)--may be useful for preventing or mitigating endothelial dysfunction. In vitro and clinical data show that TZDs can limit thrombotic, inflammatory, and oxidative changes that contribute to endothelial dysfunction. For example, TZDs have been shown to lower blood levels of plasminogen activator inhibitor-1, a prothrombotic substance, in patients with diabetes or insulin resistance. In obese patients, TZD treatment can improve vascular reactivity and reduce monocyte expression of nuclear factor kappa-B, a transcription factor that contributes to inflammation and oxidative damage. In patients with overt diabetes or insulin resistance, TZD treatment can lower blood levels of C-reactive protein and interleukin-6, markers of inflammation and cardiovascular risk. These beneficial effects of TZDs may help to decrease the risk of vascular damage and atherosclerosis in patients with insulin resistance or diabetes.
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PMID:Insulin resistance and endothelial dysfunction in atherosclerosis: implications and interventions. 1261 87

Inflammation and smoking are associated with risk of cardiovascular disease, but not much is known yet about their relationship. We studied in 15 smoking and 15 nonsmoking patients with coronary artery disease (CAD) and in 15 smoking and 15 nonsmoking healthy subjects the relationships with the inflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha). IL-6 and TNF-alpha were significantly higher in patients than in controls, both in smokers and in nonsmokers. Smoking only had a significant effect on IL-6, and mainly in the controls. In conclusion, inflammation is affected by both smoking and cardiovascular disease.
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PMID:The association between inflammation markers, coronary artery disease and smoking. 1261 81

Cardiovascular disease (CVD) is the leading cause of mortality in end-stage renal disease (ESRD) patients and there is emerging evidence that genetic factors may contribute to the development of atherosclerosis. Myeloperoxidase (MPO) is an abundant enzyme involved in the production of free radicals. A functional G-->A single nucleotide polymorphism (SNP) has been identified at position -463, where the A allele is associated with lower MPO expression. To analyze the association between this SNP and inflammation, oxidative stress, and CVD, we studied a cohort of 155 ESRD patients (52 +/- 1 years, 62% males, 22% diabetics) shortly before the initiation of dialysis treatment. CVD was defined by medical history criteria; plasma interleukin-6 (IL-6) was used as a marker of inflammation, and plasma pentosidine as an estimation of oxidative protein damage. DNA from leukocytes was used for genotyping, performed by the pyrosequencing reaction. Only five patients (3%) had the genotype AA at the -463 position, whereas 38 (25%) had the GA and 112 (72%) had the GG genotype. No differences were noted in plasma IL-6 levels between the genotype groups, whereas the pentosidine levels were higher in the GG group (28.4 pmol/mg albumin [range, 8.5 to 123 pmol/mg albumin]) compared to the other two groups (21.4 pmol/mg albumin [range, 7.6 to 384 pmol/mg albumin; P < 0.05]). Patients with the GG genotype had a higher prevalence of positive serology for Chlamydia pneumoniae (51%) when compared to the carriers of the A allele (24%) (P < 0.05). The prevalence of CVD was lower in the AA (0%) and GA genotypes (18%), compared to the GG genotype (35%). The GG genotype was still associated with CVD after correction for age, diabetes, smoking, malnutrition, and inflammation. Our findings suggest that the -463 G-->A SNP, which supposedly results in lower MPO activity, is associated with a lower prevalence of CVD in ESRD patients. It could be speculated that this effect is mediated by a decreased oxidative stress due to lower production of free radicals.
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PMID:A functional variant of the myeloperoxidase gene is associated with cardiovascular disease in end-stage renal disease patients. 1284 78

Obesity is associated with an increased risk of developing insulin resistance, Type 2 diabetes, and cardiovascular disease. Reports have suggested that adipose tissue-derived cytokines such as tumor necrosis factor-alpha, interleukin-6 and interleukin-8 could be involved in the development of these health complications. Since estrogen has been suggested to attenuate the development of atherosclerosis and cardiovascular disease, we investigated whether ovariectomy affected the production and release of these three adipose tissue-derived cytokines with and without estrogen replacement in vivo and in vitro. Female Wistar rats were submitted to either a) ovariectomy, b) ovariectomy and estrogen replacement, or c) sham operation. After five months, animals were sacrificed and parametrial adipose tissue was removed and incubated for up to 24 hours with either interleukin-1beta (IL-1beta) (5 micro g/l), dexamethasone (50 nM) or estrogen (50 nM). Ovariectomy significantly increased interleukin-6 gene expression (p < 0.05) as well as interleukin-8 protein levels (p < 0.05) and gene expression (p < 0.05) in the adipose tissue, and estrogen replacement significantly reversed this increase (p < 0.05). However, no direct effects of estrogen were found in in vitro adipose tissue incubations. Neither ovariectomy nor estrogen replacement had any effects on tumor necrosis factor-alpha protein levels or gene expression. In conclusion, estrogen-deficient rats were found to have increased production of interleukin-6 and interleukin-8, which could be attenuated by estrogen-replacement. Since estrogen is suggested to be anti-atherosclerotic, this effect might be caused by a reduction in cytokine production from the adipose tissue.
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PMID:Estrogen reduces pro-inflammatory cytokines in rodent adipose tissue: studies in vivo and in vitro. 1273 73

Inflammation plays a central role in the pathogenesis of many forms of vascular disease, including atherosclerosis. Atherogenesis begins with endothelial damage, and the damaged endothelium expresses adhesion molecules, chemokines, and proinflammatory cytokines that direct atherosclerotic plaque formation and spill into the circulation as biomarkers of atherosclerotic disease risk. Menopausal hormone therapy, including a variety of estrogen preparations with or without a progestin, has negative modulatory effects on most of these soluble inflammatory markers, including E-selectin, vascular cell adhesion molecule-1, intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha, inconsistent effects on interleukin-6, and stimulatory effects on transforming growth factor-beta, a vasoprotective cytokine. In contrast, C-reactive protein, a circulating proinflammatory cytokine produced in both liver and atherosclerotic arteries, increases in response to oral conjugated estrogens but not to transdermal estrogen. Although C-reactive protein is clearly linked to increased cardiovascular disease risk in women, the hormone-induced rise in this biomarker is not associated with increased risk and may be related to a first-pass effect of C-reactive protein production in the liver after oral estrogen absorption. Many important questions about the effects of ovarian hormones on vascular inflammation and the pathogenesis of vascular disease cannot be answered in human subjects. Insights from fundamental mechanistic studies in animal models are needed to delineate the cellular/molecular events that determine whether these hormones protect or injure blood vessels.
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PMID:Hormone replacement therapy and inflammation: interactions in cardiovascular disease. 1291 55

Long-term arsenic exposure is associated with an increased risk of vascular diseases including ischemic heart disease, cerebrovascular disease, and carotid atherosclerosis. The pathogenic mechanisms of arsenic atherogenicity are not completely clear. A fundamental role for inflammation in atherosclerosis and its complications has become appreciated recently. To investigate molecular targets of inflammatory pathway possibly involved in arsenic-associated atherosclerosis, we conducted an exploratory study using cDNA microarray and enzyme-linked immunosorbent assay to identify genes with differential expression in arsenic-exposed yet apparently healthy individuals. As an initial experiment, array hybridization was performed with mRNA isolated from activated lymphocytes of 24 study subjects with low (0-4.32 microg/L), intermediate (4.64-9.00 microg/L), and high (9.60-46.5 microg/L) levels of blood arsenic, with each group comprising eight age-, sex-, and smoking frequency-matched individuals. A total of 708 transcripts of known human genes were analyzed, and 62 transcripts (8.8%) showed significant differences in the intermediate or high-arsenic groups compared with the low-level arsenic group. Among the significantly altered genes, several cytokines and growth factors involving inflammation, including interleukin-1 beta, interleukin-6, chemokine C-C motif ligand 2/monocyte chemotactic protein-1 (CCL2/MCP1), chemokine C-X-C motif ligand 1/growth-related oncogene alpha, chemokine C-X-C motif ligand 2/growth-related oncogene beta, CD14 antigen, and matrix metalloproteinase 1 (interstitial collagenase) were upregulated in persons with increased arsenic exposure. Multivariate analyses on 64 study subjects of varying arsenic exposure levels showed that the association of CCL2/MCP1 plasma protein level with blood arsenic remained significant after adjustment for other risk factors of cardiovascular diseases. The results of this gene expression study indicate that the expression of inflammatory molecules may be increased in human subjects after prolonged exposure to arsenic, which might be a contributory factor to the high risk of atherosclerosis in arseniasis-endemic areas in Taiwan. Further multidisciplinary studies, including molecular epidemiologic investigations, are needed to elucidate the role of arsenic-associated inflammation in the development of atherosclerosis and subsequent cardiovascular disease.
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PMID:Gene expression of inflammatory molecules in circulating lymphocytes from arsenic-exposed human subjects. 1292 51


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