Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NEX9 (reductase)
 26,410 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expression of both pro- and anti-inflammatory mediators are influenced by various factors such as rheumatic diseases, myocardial infarction, angina, aging, obesity and pharmacotherapy. This has therapeutic consequences. Clearance of highly bound and efficiently metabolized drugs may be reduced in the presence of inflammation amounting to increased circulating drug concentration. In the meantime, various cardiovascular receptors are down-regulated in the presence of pro-inflammatory mediators. Consequently, conditions such as rheumatoid arthritis, aging and obesity results in reduced response to drugs such as verapamil despite increased drug concentration. The inflammatory response is a complex cascade of non-specific events resulting in excessive generation of inflammatory mediators such as cytokines, C-reactive protein and nitric oxide by cells of the innate (macrophages, monocytes, neutrophils) and adaptive (T-lymphocytes) arms of the immune system. T-lymphocytes secrete various pro- and anti-inflammatory cytokines during an inflammatory event. In general, two distinct subpopulations of these T-helper cells exist, anti-inflammatory Th2 and pro-inflammatory Th1. As a common rule, Th1 cytokines suppress Th2 and vice-versa. Hence, a balance of these activities is desired. Drugs such as antirheumatoid agents, angiotensin II blockers and hydroxymethyl-glutaryl-CoA reductase inhibitor (statin) may help to restore the Th1/Th2 balance. In general, at least for some conditions, the challenge of therapeutic drug monitoring will be more useful if expression of inflammatory mediators is also taken into account. In addition, some of the intersubject variation in pharmacotherapy and clinical trails may be attributed to variations in the inflammatory mediator's concentration. A detail list of conditions and drugs that influence expression of the inflammatory mediators are provided and potential therapeutic consequences are discussed.
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PMID:Drug disease interactions: role of inflammatory mediators in disease and variability in drug response. 1640 7

We investigated the pleiotropic effects of a calcium antagonist (amlodipine) on early atherosclerosis development in the presence and absence of an HMG-CoA-reductase inhibitor (atorvastatin) in apolipoprotein E*3-Leiden/human C-reactive protein (E3L/CRP) transgenic mice. Male E3L/CRP transgenic mice were fed a cholesterol-containing diet either with or without amlodipine and/or atorvastatin. After 31 weeks, atherosclerosis in the aortic root area was quantified. Treatment with amlodipine did not significantly lower blood pressure, but resulted in a 43% reduction (P < 0.03) of lesion area as compared with the untreated group. Treatment with atorvastatin resulted in an 80% reduction of lesion area as compared with the untreated group (P < 0.001). Combined treatment with amlodipine and atorvastatin decreased the lesion area by 93%, significantly more than either treatment alone (P < 0.008). Plasma C-reactive protein levels were mildly elevated, on average 10 +/- 6 mg/L, and did not differ between groups, neither on baseline nor during treatment. Treatment with amlodipine, independently of blood pressure lowering, reduced atherosclerosis development in E3L/CRP mice. Atorvastatin had a strong anti-atherosclerotic effect, whereas co-treatment with amlodipine enhanced this effect significantly. Plasma C-reactive protein levels were not affected by any of the three treatments.
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PMID:Anti-atherosclerotic effect of amlodipine, alone and in combination with atorvastatin, in APOE*3-Leiden/hCRP transgenic mice. 1642 91

Clinical studies conducted since the 1970s by the pediatric diabetology group of the Free University of Brussels have demonstrated that screening for subclinical retinopathy, neuropathy and nephropathy should be started at puberty and at least 3 years after the diabetes diagnosis. The goal is to detect early abnormalities responsible for subclinical disorders that can be reversed by improved metabolic control, thus preventing the occurrence of irreversible potentially incapacitating lesions. A 1974 retinal fluorescein angiography study showed that the development of microaneurysms, which are irreversible lesions, could be preceded by fluorescein leakage due to disruption of the blood-retinal barrier. Risk factors for early retinopathy include: duration of diabetes, age at diagnosis (with younger children having longer times to retinopathy), puberty and sex (with onset one year earlier in girls than in boys), long-term bad metabolic control over several years, high cholesterol levels and excessive body mass index (BMI). On the other hand, rapid improvement of diabetic control may worsen diabetic retinopathy (1985). Minimal EEG abnormalities were found in relationship to frequent and severe hypoglycemic comas and/or convulsions and retinopathy (1979). Desynchronization of action potentials in distal nerve fibers preceded conduction velocity slowing (1981). A single high glycated hemoglobin value was associated with peroneal motor nerve conduction slowing (1985), which was not observed in the femoral nerve (1987). Sympathetic skin response (1996) and statistical analysis of heart rate variability (2001) could have some interest for the diagnosis of early diabetic autonomic neuropathy. Early microproteinuria is of mixed origin, being both glomerular (microalbumin) and tubular (Beta2-microglobulin). Exercise testing to exhaustion did not provide additional information than the basal excretion (1976). Microtransferrinuria (1984) and urinary acid glycosaminoglycans output (2001) could also be predictive markers of glomerular dysfunction. Physical training reduced exercise-related proteinuria by half (1988). High levels of serum lipoprotein (a) were not associated with the presence of subclinical complications (1996). On the other hand, ultra sensitive C-reactive protein could be an interesting indicator for the risk of developing early complications (2002). Poor metabolic control was associated with higher levels of triglycerides, total cholesterol, LDL cholesterol and apolipoprotein B (1990). Decreased gluthatione peroxidase, gluthatione reductase and of vitamin C levels, denoting moderate oxidative stress, were found (1996), although there was no evidence of increased LDL cholesterol peroxidation (1998). Erythrocytes exhibited increased glycolytic activity and neutrophils decreased migration in relationship with metabolic control (1992). The degree of metabolic control influenced serum triiodothyronine levels (1985), magnesium concentrations (1999) and infection by Helicobacter Pylori (1997). Insulin therapy could activate the complement pathway if intermediate and long-acting insulin preparations without protamine sulphate are used (1992) and provoke higher BMI in adolescents on 4 insulin injections (1988). Well-being was inversely related to glycated hemoglobin levels (1997).
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PMID:Screening for subclinical complications in young type 1 diabetic patients: experience acquired in Brussels. 1643 30

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are potent cholesterol-lowering drugs. In addition to their cholesterol-lowering properties, statins exert a number of so-called 'pleiotropic', vasculoprotective actions that include improvement of endothelial function, increased nitric oxide (NO) bioavailability, antioxidant properties, stabilisation of atherosclerotic plaques, regulation of progenitor cells, inhibition of inflammatory responses and immunomodulatory actions. Pleiotropic actions of statins may have potential clinical impact in vascular disease beyond cholesterol lowering. The ongoing Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), for example, tests the effects of statins in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol (LDL-C) and elevated high-sensitivity C-reactive protein (hs-CRP). Additionally, previous studies have shown that although cholesterol is not an established stroke risk factor, statin therapy is associated with a reduction in the incidence of strokes. It is known that sudden withdrawal of statin treatment may acutely impair vascular function and increase morbidity and mortality in patients with vascular disease. Furthermore, the anti-inflammatory effects of statins may have clinical impact in a number of non-vascular conditions including multiple sclerosis and rheumatoid arthritis.
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PMID:Statins: potential new indications in inflammatory conditions. 1650 22

Hyperhomocysteinemia is considered an independent risk factor for atherosclerosis. The present study was designed to assess the effect of high level of serum homocysteine on other cardiovascular risk factors and markers in rats and to study its mode of action in initiating atherosclerosis. To address this issue, four different doses of methionine (0.1 g/kg, 0.25 g/kg, 0.5 g/kg, 1 g/kg) were orally administered to four groups (Group II, III, IV, V respectively) of rats (6 rats in each group) for a period of 8 weeks to get different level of homocysteine in serum. Group I was administered with saline and served as control. Our results revealed that the level of Total cholesterol, Triglyceride, and Oxidized low-density lipoproteins increased significantly with the increase in the level of serum homocysteine. The levels of Resistin, C-reactive protein and cysteinyl-leukotrienes were found to be significantly high in Group IV (P<0.001 vs Group I) and Group V (P<0.001 vs Group I) at 8 weeks. Total antioxidant capacity and nitrite/nitrate level in serum showed negative correlation with the increased dose of methionine. The mRNA expression and the enzyme activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase significantly increased only in livers of rats of Group V. Furthermore, high mRNA expression of P2 receptors and caveolin were found in aorta of rats administered with high dose of methionine (Group IV and V at 8 weeks). Data obtained from in-vitro effect of homocysteine on isolated aortic arch also showed induction in P2 receptors and caveolin with the increase in the concentration of homocysteine. These findings collectively suggest that hyperhomocysteinemia initiates atherosclerosis by modulating the cholesterol biosynthesis and by significantly inducing the level of other cardiovascular risk factors and markers, which play important role in initiating atherosclerosis.
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PMID:Effect of hyperhomocysteinemia on cardiovascular risk factors and initiation of atherosclerosis in Wistar rats. 1770 35

Molecular differences among the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) give rise to some important differences in their properties, including their anti-atherogenic and anti-inflammatory actions (among the so-called pleiotropic effects) - differences that may help to account for variation in clinical efficacy and safety among the available drugs of this class. The question of whether the clinical benefit of statins such as atorvastatin in reducing cardiovascular events in individuals with elevated cholesterol levels results from direct anti-atherogenic effects in addition to cholesterol-lowering-dependent effects cannot be conclusively answered at present. However, the available evidence suggests that these actions should be considered further, especially in some clinical situations such as acute coronary syndrome where an anti-inflammatory effect could conceivably have a greater role. In the case of atorvastatin, various direct anti-atherogenic effects have been demonstrated. These effects include modification of endothelial dysfunction, inflammatory processes and lipid oxidation, and a possible direct effect on the composition of atheromatous plaques, which together may have a positive influence on the development of atherosclerosis and its subsequent progression (e.g. on the reduction of carotid intima media thickness and regression of atheromas noted in studies with intensive atorvastatin therapy [80 mg/day]). In terms of its effects on endothelial function, improvements in flow-mediated endothelium-dependent vasodilatation have been observed as early as 2 weeks after starting atorvastatin treatment. This effect does not appear to be quantitatively correlated with lowering of low-density lipoprotein-cholesterol (LDL-C) as greater improvements in endothelial function versus ezetimibe/simvastatin have been noted with atorvastatin despite comparable reductions in LDL-C. Atorvastatin has also been shown to reduce levels of the inflammatory marker C-reactive protein; in comparative studies, this effect proved to be superior to that of simvastatin or pravastatin and equivalent to that of rosuvastatin. In other studies, atorvastatin has been found to inhibit the in vitro oxidation of LDL - an effect that appears to be due mainly its active hydroxy metabolite - and to reduce various oxidative stress markers in hypercholesterolaemic patients. In addition, there is evidence that atorvastatin is able to modify the composition of atherosclerotic plaques and their inflammatory status via a series of effects, mostly involving tissue factors.
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PMID:Effects of atorvastatin on the different phases of atherogenesis. 1791 May 18

Statin-induced inhibition ofHMG-CoA reductase reduces cholesterol production and prevents the formation of many non-steroidal isoprenoid compounds, such as farnesylpyrophosphate and geranylgeranylpyrophosphate, that act as lipid attachments for the post-translational modification of various proteins, including the G-proteins and transcription factors involved in a number of cell processes. However, the blockade of isoprenylation elicited by statin treatment also has biological effects on cell function that go beyond the decrease in cholesterol synthesis: these are the so-called "pleiotropic" effects that mainly relate to vascular function. Endothelial dysfunction is an independent predictor of cardiovascular events that correlates with inflammation markers/mediators and robust predictors of cardiovascular diseases such as increased high-sensitivity C-reactive protein levels. The results of in vivo and in vitro studies indicate that the statins have beneficial effects unrelated to cholesterol lowering, such as improving endothelial function, increasing myocardial perfusion, and enhancing the availability of nitric oxide. This review describes the pleiotropic effects of statins that may be involved in modulating/preventing endothelial dysfunction and inflammatory processes, as well as the cellular and molecular mechanisms through which they improve endothelial function.
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PMID:The role of HMG-CoA reductase inhibition in endothelial dysfunction and inflammation. 1807 8

In spite of a large number of studies on the use of HMG-CoA-reductase inhibitors (statins) in treatment of different forms of coronary artery disease, the efficacy of their early administration in acute coronary syndrome (ACS) is still unclear. The purpose of the present investigation was to study the effects of medium doses (40 mg per day) of simvastatin on the clinical course of ACS and blood levels of C-reactive protein (CRP) and lipids in ACS patients to whom the drug was administered on the first day of the disease. One hundred and eight patients with ACS were randomized into two groups: the control group receiving standard therapy, and the main group receiving in addition 40 mg of simvastatin beginning on the first day of the disease. Blood levels of lipids and CRP were measured by a precise qualitative technique on the first and fourteenth days of the disease. The clinical course of the disease was evaluated during six months from the first day of hospital stay. Mean CRP level decreased significantly within two weeks in the group of patients receiving simvastatin (from 14.9 +/- 9.7 to 7.6 +/- 6.0 mg/l; p = 0.02). In the control group CRP concentration decreased less and not significantly (from 16.1 +/- 7.3 to 13.2 +/- 6.8 mg/l; p = 0.18). Two main types of the dynamics of CRP level were revealed in the ACS patients. Most patients in both groups displayed a decrease in CRP level by the fourteenth day of the disease. At the same time, in some patients CRP level grew during this period, and these patients had stenocardia and required repeated hospital admissions due to ACS recurrence significantly more frequently during the following six months (relative risk 1.4; 95% confidence interval 1.1 to 1.8). The frequency of postinfarction stenocardia was the most substantial and significant clinical difference between the groups (50.9% in the control group, and 23.6% in the main group, p = 0.04). Thus, early therapy with simvastatin in ACS lowers SRP level and the frequency of postinfarction stenocardia. The elevation of CRP level during the first two weeks of the disease is a poor prognostic sign.
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PMID:[The effects of early application of simvastatin on C-reactive protein level, blood lipids, and the clinical course of acute coronary syndrome]. 1821 56

Type 2 diabetes mellitus is associated with elevated plasma triglyceride levels, low high-density lipoprotein cholesterol, and a high incidence of cardiovascular disease. Hydroxymethylglutaryl-coenzyme A reductase inhibitors and fibrates are frequently used in the treatment of diabetic dyslipidemia, but their specific impact on the inflammation processes involved in atherosclerosis remains to be fully characterized. The objective of this 2-group parallel study was to investigate the differential effects of a 6-week treatment with either atorvastatin 20 mg/d alone (n = 19) or micronized fenofibrate 200 mg/d alone (n = 19) on inflammation, cell adhesion, and oxidation markers in type 2 diabetes mellitus subjects with marked hypertriglyceridemia. In addition to the expected changes in lipid levels, atorvastatin decreased plasma levels of C-reactive protein (-26.9%, P = .004), soluble intercellular adhesion molecule 1 (-5.4%, P = .03), soluble vascular cell adhesion molecule 1 (-4.4%, P = .008), sE-selectin (-5.7%, P = .02), matrix metalloproteinase 9 (-39.6%, P = .04), secretory phospholipase A(2) (sPLA(2)) (-14.8%, P = .04), and oxidized low-density lipoprotein (-38.4%, P < .0001). On the other hand, fenofibrate had no significant effect on C-reactive protein levels and was associated with reduced plasma levels of sE-selectin only (-6.0%, P = .04) and increased plasma levels of sPLA(2) (+22.5%, P = .004). These results suggest that atorvastatin was potent to reduce inflammation, oxidation, and monocyte adhesion in type 2 diabetes mellitus subjects with marked hypertriglyceridemia, whereas fenofibrate decreased sE-selectin levels only and was associated with an elevation of sPLA(2) levels.
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PMID:Differential effect of atorvastatin and fenofibrate on plasma oxidized low-density lipoprotein, inflammation markers, and cell adhesion molecules in patients with type 2 diabetes mellitus. 1824 11

The pathogenesis of atherosclerosis involves multiple cellular events, including endothelial cell dysfunction, inflammation, proliferation of vascular smooth muscle cells and matrix alteration that is subsequently characterized by hardening, thickening, loss of elasticity and, finally, a reduction in the vessel's lumen. Leptin, a peptide hormone, is produced by adipocytes, and the majority of obese individuals have high plasma leptin concentrations. Leptin regulates food intake as well as metabolic function. Originally thought to be a satiety factor, leptin is a pleiotropic molecule. In addition to its metabolic effects, leptin regulates the production of several pro- and anti-inflammatory cytokines by activating immune cells. It is associated with increased plasma C-reactive protein concentrations, vascular proliferation, calcification and decreased arterial distensibility. Leptin also increases oxidative stress. Moreover, leptin contributes to increases in blood pressure, and thus, probably plays an important role in the initiation and progression of atherosclerosis. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) lower lipid concentrations and also decrease endothelial apoptosis, inhibit smooth muscle cell proliferation, and lower concentrations of C-reactive protein and proinflammatory cytokines; moreover, it is now known that statins can inhibit leptin release by adipocytes. Therefore, statins have been shown to be beneficial in atherosclerosis. The present review mainly focuses on the various evidence that suggest a potential atherogenic mechanism of leptin, and also briefly addresses the beneficial role of statins in atherosclerosis.
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PMID:Role of leptin in atherogenesis. 1865 Oct 16


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