Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogen and hormone replacement therapies are being tested to prevent the incidence of cardiovascular disease in postmenopausal women. In spite of the evidence from several epidemiological studies suggesting that estrogens protect against atherosclerosis and associated diseases, controversy exists. Moreover, it is important to develop synthetic compounds that achieve the beneficial effects of estrogens on the cardiovascular system while minimizing such undesirable effects on other tissues as the increased risk of endometrial and breast cancer. Some drugs that modulate estrogen function in a tissue-specific manner (Selective Estrogen Receptor Modulators; SERMs) have been discovered and are currently being used in clinical practice. An example of these is raloxifene. Clinical and experimental data support the consideration of endothelium as a target for estradiol and other sexual hormones. Among other actions, estradiol has been implicated in the control of prostacyclin production through cyclooxygenases (COX) regulation in endothelial cells. Prostacyclins are powerful vasodilators and potent inhibitors of platelet aggregation which are produced from free arachidonic acid through the catalytic activity of two COX: COX-1 and COX-2. Together, these COX represent the main control mechanism for prostacyclin production. Although several non-specific COX inhibitors have been available for decades (aspirin, indomethacin, ibuprofen), COX-2 selective inhibitors have been commercialized only within the last few years, thus making it possible to increase the study and treatment of different disorders. This review will discuss clinical and experimental data that document the endothelial effects of estradiol and SERMs on prostacyclin production and COX regulation, their vascular consequences, and their possible interactions with COX inhibitors.
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PMID:Cyclooxygenases regulation by estradiol on endothelium. 1645 37

Cardiovascular disease is the leading cause of death among women in the U.S., exceeding breast cancer mortality in women of all ages. Women present with cardiovascular disease a decade after men, and this has been attributed to the protective effect of female ovarian sex hormones that is lost after menopause. Animal and observational studies have shown beneficial effects of hormone therapy when it is initiated early in the perimenopausal period or before the development of significant atherosclerosis. However, randomized, placebo-controlled trials in older women have not shown any benefit in either primary prevention or secondary prevention of cardiovascular events, with a concerning trend toward harm. This review outlines the lessons learned from the basic science, animal, observational, and randomized trials, and then summarizes yet-unanswered questions of hormone therapy and cardiovascular risk.
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PMID:Hormone replacement therapy and the cardiovascular system lessons learned and unanswered questions. 1668 98

Basic calcium phosphate (BCP) and calcium pyrophosphate dihydrate crystals are the most common types of pathologic calcium-containing crystals. Although these crystals long have been associated with a variety of rheumatic syndromes, recent evidence implicates BCP crystals in the pathogenesis of breast cancer and atherosclerosis. Although understanding of molecular mechanisms involved in generating these pathologic effects has been advanced significantly in recent years, they still are understood incompletely. Such advances are essential to the ongoing search for effective therapies for crystal-associated diseases.
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PMID:Calcium crystal deposition diseases: update on pathogenesis and manifestations. 1671 85

The Life Span Study of Japanese atomic bomb survivors demonstrates that radiation exposure significantly increased the risk of developing ischemic heart disease, in particular myocardial infarction. Similarly, epidemiologic investigations in very large populations of patients who had received postoperative radiotherapy for breast cancer or for peptic ulcer demonstrate that radiation exposure of the heart with an average equivalent single dose of approximately 2 Gy significantly increased the risk of developing ischemic heart disease more than 10 years after irradiation. These epidemiologic findings are compatible with radiobiologic data on the pathogenesis of radiation-induced heart disease in experimental animals. The critical target structure appears to be the endothelial lining of blood vessels, in particular arteries, leading to early functional alterations such as pro-inflammatory responses and other changes, which are slowly progressive. Research should concentrate on the interaction of these radiation-induced endothelial changes with the early stages of age-related atherosclerosis to develop criteria for optimizing treatment plans in radiotherapy and also potential interventional strategies.
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PMID:Radiation-induced cardiovascular diseases: is the epidemiologic evidence compatible with the radiobiologic data? 1718 62

Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXR agonists are effective for treatment of murine models of atherosclerosis, diabetes, and Alzheimer's disease. Recently we observed that LXR agonists suppressed proliferation of prostate and breast cancer cells in vitro and treatment of mice with the LXR agonist T0901317 suppressed the growth of prostate tumor xenografts. LXR agonists appear to cause G1 cell cycle arrest in cells by reducing expression of Skp2 and inducing the accumulation of p27(Kip). T0901317 induced expression of ATP-binding cassette transporter A1 (ABCA1) and delayed the progression of androgen-dependent human prostate tumor xenografts towards androgen-independency in mice. Phytosterols, the plant equivalent of mammalian cholesterol, have recently been shown to be agonists for LXRs. beta-Sitosterol and campesterol, the two most common phytosterols, suppressed proliferation of prostate and breast cancer cells. The anticancer activity of phytosterols may be due to LXR signaling. This review examines the potential use of LXR signaling as a therapeutic target in prostate and other cancers.
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PMID:Modulation of liver X receptor signaling as novel therapy for prostate cancer. 1737 49

Guggulsterone is a plant polyphenol traditionally used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, possibly through an anti-inflammatory mechanism. Whether this steroid has any role in cancer is not known. In this study, we found that guggulsterone inhibits the proliferation of wide variety of human tumor cell types including leukemia, head and neck carcinoma, multiple myeloma, lung carcinoma, melanoma, breast carcinoma, and ovarian carcinoma. Guggulsterone also inhibited the proliferation of drug-resistant cancer cells (e.g., gleevac-resistant leukemia, dexamethasone-resistant multiple myeloma, and doxorubicin-resistant breast cancer cells). Guggulsterone suppressed the proliferation of cells through inhibition of DNA synthesis, producing cell cycle arrest in S-phase, and this arrest correlated with a decrease in the levels of cyclin D1 and cdc2 and a concomitant increase in the levels of cyclin-dependent kinase inhibitor p21 and p27. Guggulsterone-induced apoptosis as indicated by increase in the number of Annexin V- and TUNEL-positive cells, through the downregulation of anti-apoptototic products. The apoptosis induced by guggulsterone was also indicated by the activation of caspase-8, bid cleavage, cytochrome c release, caspase-9 activation, caspase-3 activation, and PARP cleavage. The apoptotic effects of guggulsterone were preceded by activation of JNK and downregulation of Akt activity. JNK was needed for guggulsterone-induced apoptosis, inasmuch as inhibition of JNK by pharmacological inhibitors or by genetic deletion of MKK4 (activator of JNK) abolished the activity. Overall, our results indicate that guggulsterone can inhibit cell proliferation and induce apoptosis through the activation of JNK, suppression of Akt, and downregulation of antiapoptotic protein expression.
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PMID:Guggulsterone inhibits tumor cell proliferation, induces S-phase arrest, and promotes apoptosis through activation of c-Jun N-terminal kinase, suppression of Akt pathway, and downregulation of antiapoptotic gene products. 1747 22

Plasminogen activator inhibitor type I (PAI-1) plays a central role in metastatic behavior by increasing cells' migratory capacities as shown in several tumoral cell lines. Moreover, in vivo high expression of this factor helps tumoral growth, both by its role in extracellular matrix remodeling and by favoring angiogenesis. High levels of PAI-1 are correlated with bad prognosis in several cancers, particularly in breast cancer. The effect of PAI-1 upon angiogenesis is also involved in atherosclerosis, in which high levels of PAI-1 expression are observed. Breast carcinoma MDA MB 231 cells are known for both having important metastatic capacities and expressing high levels of PAI-1. We have demonstrated in these cells that the transfection of PAI-1 specific small interfering RNAs (siRNA) specifically inhibited the expression of this factor by 91%. We evaluated siRNA activity by determining PAI-1 mRNA level, as well as intracellular and extracellular PAI-1 protein by using RT Q-PCR, Western blot and ELISA analyses, respectively. Data confirmed inhibition at mRNA levels (primary aim of interference), intracellular protein, and secreted PAI-1, the latter being operative successfully in the cell microenvironment. The lipidic vector Delivery Liposomes System (DLS) used was adapted to siRNA delivery as observed by particle size distribution analysis, confocal microscopy and transfection into MDA MB 231, in the presence of serum. SiRNA activity was clearly detected at concentrations as low as 10 nM. Moreover, the low cytotoxicity of this vector makes it a good candidate for future in vivo siRNA delivery.
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PMID:Inhibition of PAI-1 expression in breast cancer carcinoma cells by siRNA at nanomolar range. 1750 45

The objective of this study was to evaluate the scientific evidence on flaxseed, including expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. Electronic searches were conducted in 9 databases, 20 additional journals (not indexed in common databases), and bibliographies from 50 selected secondary references. No restrictions were placed on the language or quality of the publications. All literature collected pertained to efficacy in humans, dosing, precautions, adverse effects, use in pregnancy/lactation, interactions, alteration of laboratory assays, and mechanisms of action. Standardized inclusion/exclusion criteria are used for selection. Grades were assigned using an evidence-based grading rationale. A review of the literature on flaxseed yielded 13 categories for which flaxseed had been studied in humans, including constipation/laxative, attention-deficit hyperactivity disorder, hyperlipidemia, atherosclerosis/coronary artery disease, breast cancer, cyclic mastalgia (breast pain), menopausal symptoms, hyperglycemia/diabetes, hypertension, lupus nephritis, human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), and prostate cancer. Most of the available evidence investigates the efficacy of alpha-linoleic acid found in flaxseed compared with fish oil, and almost all of the available studies are poor quality. Although flaxseed and flaxseed oil have several promising future uses, the available literature does not support recommendation for any condition at this time.
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PMID:Flax and flaxseed oil (Linum usitatissimum): a review by the Natural Standard Research Collaboration. 1776 Nov 28

Adhesion of cancer cell to endothelial cells and the subsequent trans-endothelial migration are key steps in metastasis. However, the identities of the molecules mediating cancer cell/endothelial cell interaction are still not fully understood. In this study, we tested the hypothesis that lectin-like oxidized-low-density lipoprotein (oxLDL) receptor-1 (LOX-1), a key mediator of vascular inflammation and atherosclerosis expressed on endothelial cell surface, mediates breast cancer cell/endothelial cell interactions. We showed that up-regulation of endothelial LOX-1 by TNF-alpha promoted the adhesion and trans-endothelial migration of MDA-MB-231 breast cancer cells. Thus, endothelial LOX-1 could present a novel pathway in breast cancer metastasis.
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PMID:Up-regulation of LOX-1 expression by TNF-alpha promotes trans-endothelial migration of MDA-MB-231 breast cancer cells. 1786 83

Endothelial cell senescence and apoptosis are features of numerous human pathologies including atherosclerosis, allograft vasculopathy, heart failure, diabetic retinopathy and scleroderma. In contrast, endothelial cell activation and replication associated with vessel proliferation and angiogenesis are now therapeutic targets in other diseases such as cancer and macular dystrophy. Finally, preventive medicine, in particular cardiovascular and cancer chemoprevention, commonly involve the endothelium. Here we discuss several aspects of the interplay between endothelial cell aging, apoptosis and senescence. Further, we show novel microarray data on endothelial cells "aged" in culture, and note that many genes regulated by the aging process are also modulated by a chemopreventive anti-angiogenic and anti-apoptotic drug, N-acetyl-cysteine (NAC). Focusing on one of these genes, the leukocyte adhesion protein E-selectin, we show that E-selectin is down-modulated with time in culture and upon treatment with NAC at mRNA and protein levels. This correlates with reduced adhesion of breast cancer cells and NF-kB activation in NAC treated endothelial cells. These data underscore the effects of a chemoprevention agent in modulating parameters associated with endothelial cell aging.
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PMID:Endothelial cell aging and apoptosis in prevention and disease: E-selectin expression and modulation as a model. 1822 Aug 32


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