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)

The intake of n-3 polyunsaturated fatty acids (PUFAs) in many industrialized countries is relatively low and its increased consumption has protective and modifying effects on such diverse conditions as atherosclerosis, ventricular arrhythmias, multiple sclerosis, major depression and inflammatory and autoimmune diseases. In addition, n-3 PUFAs have been shown to alleviate pain in patients with rheumatoid arthritis, inflammatory bowel disease and in a number of other painful conditions. This has been attributed to the inhibition of pro-inflammatory eicosanoid and cytokine production by peripheral tissues. n-3 PUFAs have also been shown to inhibit eicosanoid production in glial cells, block voltage-gated sodium channels (VGSCs), inhibit neuronal protein kinases and modulate gene expression. They also appear to have mood-stabilizing and sympatholytic effects. The present article explores the possibility that, based on what is known about their neural and non-neural effects, n-3 PUFAs directly attenuate the neuronal and glial processes that underlie neuropathic and inflammatory pain.
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PMID:Could n-3 polyunsaturated fatty acids reduce pathological pain by direct actions on the nervous system? 1259 Oct 6

The role of thiazolidinediones (currently rosiglitazone and pioglitazone) in the treatment of Type 2 diabetes is firmly established. The mechanism of action involves binding to the peroxisome proliferator-activated receptor-gamma, a transcription factor that regulates the expression of specific genes especially in fat cells but also other cell types such as endothelial cells, macrophages and monocytes, vascular smooth muscle cells and colonic epithelium. Thiazolidinediones have been shown to interfere with expression and release of mediators of insulin resistance originating in adipose tissue (e.g., increased free fatty acids, decreased adiponectin) in a way that results in net improvement of insulin sensitivity (i.e., in muscle and liver). A direct or indirect effect on AMP-dependent protein kinase may also be involved. Prevention of lipid accumulation in tissues critical to glycaemia such as visceral adipocytes, liver, muscle and beta-cells at the expense of lipids accumulating at the less harmful subcutaneous site may be central to their net metabolic effect. The sustained beneficial effect of troglitazone on beta-cell function in women with previous gestational diabetes in addition to the insulin-sensitising properties point to an important role of this class of drugs in the prevention of Type 2 diabetes. Original safety concerns based on animal and in vitro studies (e.g., fatty bone marrow transformation, colonic cancer, adipogenic transdifferentiation of blood cells) remain theoretical issues but become less pressing practically with prolonged uneventful clinical use. Hepatotoxicity for troglitazone and fluid retention, which can aggravate pre-existing heart failure, are the most important side effects. In summary, with the thiazolidinediones, a novel concept for the treatment of insulin resistance and possibly preservation of beta-cell function is available that could become effective in the prevention of Type 2 diabetes. Moreover, their anti-inflammatory properties also make them interesting in the prevention and treatment of atherosclerosis and possibly other inflammatory conditions (e.g., inflammatory bowel disease). Long-term data will be necessary for a final risk-benefit assessment of these substances.
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PMID:Thiazolidinediones -- some recent developments. 1283 52

The author reviews the complex role of heat-shock proteins during the immune reaction, especially the cellular effects of heat-shock proteins during recognition processes by innate immunity. The pathogenetic role of heat-shock proteins in two multifactorial diseases, inflammatory bowel disease and atherosclerosis, is summarized. A new hypothesis is presented dealing with the "immunodeficiency burden" as the aggregate effect of the genetic polymorphisms resulting in disease susceptibility. According to this mechanism the aggregate effect of polymorphisms resulting in failure of protective immunity determines the susceptibility for the disease in the given subject, when a specific environmental factor is present.
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PMID:[Heat shock proteins as chaperones of the immune response. The optimal stress of life]. 1290 46

VCAM-1 (vascular cell adhesion molecule-1) plays an important role in the regulation of inflammation in atherosclerosis, asthma, inflammatory bowel disease and transplantation. VCAM-1 activates endothelial cell NADPH oxidase, and this oxidase activity is required for VCAM-1-dependent lymphocyte migration. We reported previously that a mouse microvascular endothelial cell line promotes lymphocyte migration that is dependent on VCAM-1, but not on other known adhesion molecules. Here we have investigated the signalling mechanisms underlying VCAM-1 function. Lymphocyte binding to VCAM-1 on the endothelial cell surface activated an endothelial cell calcium flux that could be inhibited with anti-alpha4-integrin and mimicked by anti-VCAM-1-coated beads. VCAM-1 stimulation of calcium responses could be blocked by an inhibitor of intracellular calcium mobilization, a calcium channel inhibitor or a calcium chelator, resulting in the inhibition of NADPH oxidase activity. Addition of ionomycin overcame the calcium channel blocker suppression of VCAM-1-stimulated NADPH oxidase activity, but could not reverse the inhibitory effect imposed by intracellular calcium blockage, indicating that both intracellular and extracellular calcium mobilization are required for VCAM-1-mediated activation of NADPH oxidase. Furthermore, VCAM-1 specifically activated the Rho-family GTPase Rac1, and VCAM-1 activation of NADPH oxidase was blocked by a dominant negative Rac1. Thus VCAM-1 stimulates the mobilization of intracellular and extracellular calcium and Rac1 activity that are required for the activation of NADPH oxidase.
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PMID:Calcium mobilization and Rac1 activation are required for VCAM-1 (vascular cell adhesion molecule-1) stimulation of NADPH oxidase activity. 1459 51

Inflammation is a fundamental response to tissue injury and invasion of pathogens, but it is detrimental in clinically important inflammatory disorders. Leukocytes are key players in the inflammatory response because of their antimicrobial, secretory and phagocytic activities. They are recruited to the inflamed tissue by sequential adhesive interactions between leukocytes and the endothelium that are mediated by cell-adhesion molecules (CAMs) on the surface of the interacting cells. The effects of many anti-inflammatory drugs can be ascribed, in part, to inhibition of the expression of CAMs. However, in the search for more selective and potent drugs for clinically important diseases such as multiple sclerosis, asthma, rheumatoid arthritis, inflammatory bowel disease, allergies and atherosclerosis, direct inhibition of the function of CAMs has attracted increasing interest. In recent years, the development of synthetic antagonists has provided better opportunities for drug targeting. Future advances in this field hold new prospects for therapeutic intervention in human inflammatory disorders.
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PMID:Leukocyte and endothelial cell adhesion molecules as targets for therapeutic interventions in inflammatory disease. 1465 5

Macrophages play diverse roles in host defense and in maintenance of homeostasis. Based on their ability to promote inflammatory responses, inappropriate macrophage function also contributes to numerous pathological processes, including atherosclerosis, rheumatoid arthritis and inflammatory bowel disease. Members of the nuclear receptor superfamily of ligand-dependent transcriptions factors have emerged as key regulators of inflammation and lipid homeostasis in macrophages. These include the glucocorticoid receptor (GR), which inhibits inflammatory programs of gene expression in response to natural corticosteroids and synthetic anti-inflammatory ligands such as dexamethasone. Also, in response to endogenous eicosanoids and oxysterols, respectively, peroxisome proliferator-activated receptors (PPARs) and liver X receptors (LXRs) regulate transcriptional programs involved in inflammatory responses and lipid homeostasis. Identification of their mechanisms of action should help guide the development of new therapeutic agents useful in the treatment of diseases in which macrophages play critical pathogenic roles.
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PMID:Nuclear receptor signaling in macrophages. 1469 33

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family. After activation by specific ligands, they regulate the transcription of genes involved in lipid and lipoprotein metabolism, glucose and energy homeostasis, as well as cellular differentiation. Recent studies have identified expression of the three PPARs in all cells of the arterial wall, where they control cholesterol homeostasis as well as the inflammatory response and, as a consequence, modulate atherogenesis. More generally, PPARs influence cell proliferation as well as the immune and inflammatory response in different tissues and cells. In this review, we will summarize the evidence indicating that PPARs are modulators of the inflammatory response with potential therapeutic applications not only in atherosclerosis, but potentially also in other inflammation-related diseases, such as hepatic inflammation and inflammatory bowel disease.
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PMID:Peroxisome proliferator-activated receptors and inflammation: from basic science to clinical applications. 1470 43

The nuclear factor (NF)-kappaB pathway is important for the expression of a wide variety of genes that are involved in the control of the host immune and inflammatory response, and in the regulation of cellular proliferation and survival. The constitutive activation of this pathway is associated with inflammatory and autoimmune diseases, such as asthma, rheumatoid arthritis and inflammatory bowel disease, in addition to atherosclerosis, Alzheimer's disease, cancer and diabetes. One of the key steps in activating the NF-kappaB pathway is the stimulation of the IkappaB (inhibitor of kappaB) kinases. Recent data indicate that these kinases activate the NF-kappaB pathway through distinct steps that are operative in both the cytoplasm and the nucleus. A better understanding of the mechanisms that activate this pathway provides the potential for defining new therapeutic targets that might prevent the aberrant activation of NF-kappaB in a variety of human diseases.
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PMID:IkappaB kinases: key regulators of the NF-kappaB pathway. 1510 33

This review summarizes the complex role of heat-shock proteins (Hsp) in immune reactions, especially the cellular effects of heat-shock proteins during the recognition processes by innate immunity. The role of heat-shock proteins in the pathogenesis of two multifactorial diseases, i.e. inflammatory bowel disease (IBD) and atherosclerosis is highlighted. A new hypothesis on "immunodeficiency burden" is presented. According to this hypothesis, susceptibility to any multifactorial disease in any given subject and in the presence of specific environmental factors is the aggregate effect of polymorphisms resulting in the failure of protective immunity with consequent disease.
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PMID:Immunological aspects of heat-shock proteins-the optimum stress of life. 1514 May 73

Nuclear factor-kappaB (NF-kappaB) is a major transcription factor that plays an essential role in several aspects of human health including the development of innate and adaptive immunity. The dysregulation of NF-kappaB is associated with many disease states such as AIDS, atherosclerosis, asthma, arthritis, cancer, diabetes, inflammatory bowel disease, muscular dystrophy, stroke, and viral infections. Recent evidence also suggests that the dysfunction of NF-kappaB is a major mediator of some human genetic disorders. Appropriate regulation and control of NF-kappaB activity, which can be achieved by gene modification or pharmacological strategies, would provide a potential approach for the management of NF-kappaB related human diseases. This review summarizes the current knowledge of the physiological and pathophysiological functions of NF-kappaB and its possible role as a target of therapeutic intervention
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PMID:Nuclear factor-kappaB: its role in health and disease. 1517 63


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