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)

Superoxide dismutases' (SODs) expression is altered in several diseases including Alzheimer, atherosclerosis, cancer and psoriasis. Previously, we reported a marked increase in Mn-SOD and Cu,Zn-SOD functional activity in human dermal psoriatic fibroblasts. As retinoic acid (RA) has been used in the treatment of psoriasis and a mechanism for its beneficial effects is not understood, we investigated the effects of RA on SOD mRNA and protein expression levels in human normal and psoriatic fibroblasts. Prior to RA exposure, Cu,Zn-SOD protein and mRNA levels were similar in normal compared to psoriatic fibroblasts while Mn-SOD protein and mRNA levels were increased in psoriatic cells. However, in contrast to normal fibroblasts, exposure of psoriatic fibroblasts to 1 microM RA down-regulated Mn-SOD mRNA, and also decreased Mn-SOD activity by approximately 80% with no change in Mn-SOD protein levels. In contrast, Cu,Zn-SOD protein and enzymatic activity were modestly reduced by RA treatment in both normal and psoriatic fibroblasts. Furthermore, RA treatment of psoriatic fibroblasts also caused a decrease in Cu,Zn-SOD steady-state mRNA levels. These results indicate that RA can serve as a regulatory agent to down-regulate the steady-state levels of both Mn-SOD and Cu,Zn-SOD in psoriatic cells. These findings offer a new model for the antiinflammatory activity of RA when used in the treatment of psoriasis.
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PMID:Differential regulation of Cu, Zn- and Mn-superoxide dismutases by retinoic acid in normal and psoriatic human fibroblasts. 1572 79

Cholesterol efflux from human monocyte-derived macrophages in the absence of exogenous acceptors has been described, but is unclear in mechanism. We investigated this process in relation to the expression of relevant genes, intracellular cholesterol storage and apoE secretion using drugs affecting different aspects of cholesterol metabolism. Both natural (22R-hydroxycholesterol/9-cis-retinoic acid) and synthetic (T0901317 and RO264456) LXR/RXR ligands increased ABCA1 and ABCG1 mRNAs in native macrophages and in cells loaded with acetylated LDL (acLDL). The ACAT inhibitor avasimibe increased only ABCG1 mRNA, whereas no treatment affected apoE mRNA. Avasimibe, progesterone, and natural but not synthetic LXR/RXR ligands prevented cholesterol esterification after acLDL-loading. Cholesterol efflux into acceptor-free medium was increased only by synthetic LXR/RXR ligands and avasimibe in acLDL-loaded cells. ApoE secretion was reduced by drugs affecting cholesterol trafficking but enhanced by LXR/RXR ligands. Incubation with an anti-apoE antibody virtually removed immunodetectable apoE from the medium, significantly increasing cholesterol storage and decreasing efflux. These findings indicate that in human macrophages spontaneous cholesterol efflux: (i) is not necessarily promoted by increasing intracellular free cholesterol, (ii) is increased by compounds that activate ABCA1 and, to a greater extent, ABCG1 and (iii) is only partially correlated with secretion of endogenous apoE, which acted as a cholesterol acceptor.
Atherosclerosis 2005 Apr
PMID:Pharmacological regulation of cholesterol efflux in human monocyte-derived macrophages in the absence of exogenous cholesterol acceptors. 1577 36

Retinoic acid receptor-related orphan receptor-alpha (RORalpha) (NR1F1) is an orphan nuclear receptor with a potential role in metabolism. Previous studies have shown that RORalpha regulates transcription of the murine Apolipoprotein AI gene and human Apolipoprotein CIII genes. In the present study, we present evidence that RORalpha also induces transcription of the human Apolipoprotein AV gene, a recently identified apolipoprotein associated with triglyceride levels. Adenovirus-mediated overexpression of RORalpha increased the endogenous expression of ApoAV in HepG2 cells and RORalpha also enhanced the activity of an ApoAV promoter construct in transiently transfected HepG2 cells. Deletion and mutation studies identified three AGGTCA motifs in the ApoAV promoter that mediate RORalpha transactivation, one of which overlaps with a previously identified binding site for PPARalpha. Together, these results suggest a novel mechanism whereby RORalpha modulates lipid metabolism and implies RORalpha as a potential target for the treatment of dyslipidemia and atherosclerosis.
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PMID:Identification of the human ApoAV gene as a novel RORalpha target gene. 1578 Dec 55

Fibrinogen is a plasma protein synthesized by the liver. It is composed of three chains (alpha, beta, gamma). In addition to its main function as a coagulation factor, this acute phase protein is also a risk marker for atherosclerosis. Retinoic acid receptor-related orphan receptor (ROR)alpha is a nuclear receptor modulating physiopathological processes such as cerebellar ataxia, inflammation, atherosclerosis, and angiogenesis. In this study, we identified RORalpha as a regulator of fibrinogen-beta gene expression in human hepatoma cells and in mouse liver. A putative RORalpha response element (RORE) was identified in the human fibrinogen-beta promoter. EMSA showed that RORalpha binds specifically to this RORE, and cotransfection experiments in HepG2 hepatoma cells indicated that this RORE confers RORalpha-dependent transcriptional activation to both the human fibrinogen-beta and the thymidine kinase promoters. Stable transfection experiments in HepG2 and Hep3B hepatoma cells demonstrated that overexpression of RORalpha specifically increases endogenous fibrinogen-beta mRNA levels. Chromatin immunoprecipitation experiments revealed that the fibrinogen-beta RORE is occupied by RORalpha in HepG2 cells. Thus, the human fibrinogen-beta gene is a direct target for RORalpha. Furthermore, fibrinogen-beta mRNA levels in liver and plasma fibrinogen concentrations are specifically decreased in staggerer mice, which are homozygous for a deletion invalidating the Rora gene. Taken together, these data add further evidence for an important role of RORalpha in the control of liver gene expression with potential pathophysiological consequences on coagulation and cardiovascular risk.
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PMID:The gene encoding fibrinogen-beta is a target for retinoic acid receptor-related orphan receptor alpha. 1594 50

Vascular replacement in vital organs is sometimes necessary for human life for example because of atherosclerosis. Blood vessel tissue engineering is applied for autologous transplantations to avoid graft rejections. Stem cells are used for blood vessel tissue engineering because they are the origin of smooth muscle cells, endothelial cells and fibroblasts. This paper shows that bone marrow stromal cells (BMSCs) can be induced to differentiate into the early stage of smooth muscle cells by using 0.01 microM retinoic acid. The differentiation of BMSCs to smooth muscle cells was detected by the expression of smooth muscle alpha actin (SM alpha-actin), the earliest smooth muscle cell marker. The SM alpha-actin marker expression was demonstrated using indirect immunofluorescence technique and Western blot analysis. The induction of BMSC to form early stages of smooth muscle cells in this study is appropriate for blood vessel tissue engineering because the early stage smooth muscle cells may be stimulated to develop vascular walls with endothelial cells using a co-culture system.
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PMID:Increased smooth muscle actin expression from bone marrow stromal cells under retinoic acid treatment: an attempt for autologous blood vessel tissue engineering. 1625 40

The effect of fibrates on high density lipoprotein (HDL)-cholesterol levels is suggested to be mediated by its binding to peroxisome proliferator-activated receptor-alpha (PPARalpha). Upon ligand binding, PPARalpha heterodimerizes with the 9-cis retinoic acid receptor (RXR) and it is this heterodimer which regulates gene expression. We assessed the hypothesis that a combined treatment with fibrate plus 9-cis beta-carotene-rich powder of the alga Dunaliella bardawil, as a source of 9-cis retinoic acid, would improve the drug's effect on HDL-cholesterol levels. In an open-labeled first trial, 20 fibrate-treated men with plasma HDL-cholesterol levels below 40 mg/dl were given Dunaliella capsules, providing 60 mg beta-carotene/day, containing all-trans and 9-cis beta-carotene (1:1 ratio, w/w). Twenty-two fibrate-treated patients participated in a double-blind placebo-controlled second trial. Eleven patients were treated with Dunaliella capsules, and 11 patients were treated with beta-carotene-deficient Dunaliella capsules. Following 6 weeks of the dual treatment plasma HDL-cholesterol increased by 24.5 and 12.7% in the first and second trials, respectively (P=0.002 and 0.012). The dual treatment also increased HDL-cholesterol levels in human apolipoprotein A-I transgenic mice by 87.5% (P=0.021). The results show that a combination treatment of fibrate plus 9-cis beta-carotene-rich Dunaliella powder amplifies the effect of the drug on HDL-cholesterol levels.
Atherosclerosis 2006 Nov
PMID:9-cis beta-carotene-rich powder of the alga Dunaliella bardawil increases plasma HDL-cholesterol in fibrate-treated patients. 1641 56

Retinoic acid receptor-related orphan receptor alpha (RORalpha) is a member of the nuclear receptor family. Recently, cholesterol (derivatives) has been identified as an RORalpha ligand and deorphanized this receptor. RORalpha is expressed in many tissues and is therefore a regulator of multiple biological processes. Studies of staggerer mice and in vitro assays indicate a beneficial modulatory role of RORalpha in the pathogenesis of dyslipidemia, inflammation and atherosclerosis. This paper provides an overview on the role of RORalpha in lipid metabolism and discusses its potential therapeutic option for treating lipid and inflammatory disorders leading to atherosclerosis.
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PMID:Retinoic acid receptor-related orphan receptor alpha as a therapeutic target in the treatment of dyslipidemia and atherosclerosis. 1662 64

The proinflammatory cytokine interleukin (IL)-1beta and the IL-1 receptor antagonist are expressed by atherosclerotic plaques and may be linked to the development of atherosclerosis. Existing evidence shows that retinoids and their receptors are involved in inflammatory response and that they are found in atherosclerotic plaques. In all-trans-retinoic acid (atRA)-treated human aortic smooth muscle cells (AOSMC), significant increases in IL-1beta levels were observed, compared with untreated cells. Examination of IL-1 receptor antagonist and IL-1 receptor type I levels did not show any difference between atRA-treated and -untreated AOSMC. The results show that atRA-treated AOSMC express both the precursor (33 kDa) and the active form (17 kDa) of the IL-1beta protein. atRA-treated carotid lesions showed significantly elevated IL-1beta mRNA levels (2.9 +/- 2.33) compared with untreated lesions (2.0 +/- 1.77; p < 0.05). These results support the role of atRA as a regulator of inflammation such as in atherosclerosis.
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PMID:Expression of IL-1beta, IL-1 receptor type I and IL-1 receptor antagonist in human aortic smooth muscle cells: effects of all-trans-retinoic acid. 1680 30

Soy consumption is associated with decreased incidence of chronic diseases, including cardiovascular diseases, atherosclerosis, diabetes, osteoporosis, and certain types of cancers. However, consumption of high amounts of soy isoflavones may adversely influence endocrine functions, such as thyroid function and reproductive performance, because of their structural similarity to endogenous estrogens. Nuclear receptors are a group of transcription factors that play critical roles in the regulation of gene expression and physiological functions through direct interaction with target genes. Modulation of the abundance of these receptors, such as changing their gene expression, alters the sensitivity of the target cells or tissues to the stimulation of ligands, and eventually affects the relevant physiological functions, such as growth, development, osteogenesis, immune response, lipogenesis, reproductive process, and anticarcinogenesis. A number of studies have shown that the bioactive components in soy can modify the expression of these receptors in various tissues and cancer cells, which is believed to be a key intracellular mechanism by which soy components affect physiological functions. This review summarizes the current understanding of the modulation of nuclear receptors by soy proteins and isoflavones, and focuses especially on the receptors for estrogens, progesterone, androgen, vitamin D, retinoic acid, and thyroid hormones as well as the potential impact on physiological functions.
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PMID:Nuclear receptors: potential biomarkers for assessing physiological functions of soy proteins and phytoestrogens. 1691 64

The function of gangliosides, sialic acid-containing glycolipids, on the secretion and assembly of apoB-containing lipoproteins is poorly understood. Here, we report that the GD3 synthase is involved in apoB secretion in retinoic acid (RA)-treated Chang liver cells via transcriptional induction of microsomal triglyceride transfer protein (MTP). The overexpression of GD3 synthase in Chang liver cells increases the expression of the MTP gene, but GM3 synthase-transfected cells did not. The levels of GM3 and GD3 gangliosides in each of the transfected cells were increased in the cell extract as well as the medium. In addition, GD3 synthase-transfected cells showed an increased secretion of triglyceride-enriched apoB. In contrast, the triglyceride content in GM3 synthase-transfected cells was relatively lower. Treatment with small interfering RNAs (siRNAs) and GD3 antibody decreased apoB secretion. These results indicate that plasma membrane associated GD3 play important roles in apoB secretion, and that an enhancement in GD3 levels might be a risk factor for the development of atherosclerosis by increasing the secretion of triglyceride-enriched apoB containing lipoproteins.
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PMID:Disialoganglioside GD3 increases in the secretion of apoB-containing lipoproteins. 1736 71


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