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)

In atherosclerosis and tumor initiation, inducible nitric oxide synthase (iNOS) has been implicated in the damage of vascular walls and DNA, respectively. Moderate consumption of red wine has been ascribed as a preventive for coronary heart disease; however, there has been much debate over whether the beneficial effect is from grape polyphenolic components or ethanol. We studied the interaction of grape compounds on nitric oxide (NO) production by macrophages, mediators of blood vessel damage in atherosclerosis. For the murine macrophage cell line RAW 264.7, stimulation with lipopolysaccharide and interferon-gamma led to expression of the iNOS gene and production of NO. The polyphenols quercetin and resveratrol at a micromolar range suppressed iNOS gene expression and NO production, as determined by reverse transcription-polymerase chain reaction and nitrite assay. The polyphenols were also found to be scavengers of NO in an acellular system using sodium nitroprusside under physiological conditions. Ethanol, at a moderate level, did not produce any appreciable level of reduction of iNOS or NO activity. However, its presence at 0.1 to 0.75% enhanced the effect of grape polyphenols concentration-dependently. Thus, the interaction between these components plays a significant role in the health effects of red wine, especially with respect to their effect on the NO pathway.
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PMID:Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway. 1102 Apr 57

Resveratrol (3,5,4'-trihydroxystilbene) is a naturally occurring compound shown to modulate the risk of cardiovascular degenerative diseases (atherosclerosis) and inhibit chemical carcinogenesis in rodents. Various studies have demonstrated the effect of this phytoalexin on biological mechanisms involved in cardioprotection. These include modulation of lipid turnover, inhibition of eicosanoid production, prevention of the low-density lipoprotein oxidation and inhibition of platelet aggregation. Carcinogenesis in animal models can be divided at least into three stages: initiation, promotion and progression. Initiation occurs as result of interaction of a reactive form of carcinogen with DNA. Chemical carcinogens like polycyclic aromatic hydrocarbons are metabolized to reactive species by cytochrome P450 dependent enzymes activated through aryl hydrocarbon (Ah) receptor. The inhibition of tumor initiation by resveratrol most probably occurs through preventing the activation of Ah receptor. Resveratrol affects also several factors involved in tumor promotion and progression. Since tumor promoting agents alter the expression of genes whose products are associated with inflammation, chemoprevention of cardiovascular diseases and cancer may share the same common mechanisms. This includes principally modulation of the expression of growth factors and cytokines. Recently, chemopreventive properties of resveratrol have been associated with the inhibition of NF-kappaB. This transcription factor is strongly linked to inflammatory and immune responses, regulation of cell proliferation and apoptosis, thus it is important for tumor development and many other diseases including atherosclerosis. Although the mechanisms by which resveratrol interferes with the activation of NF-KB are not clear, it seems that inhibition of its degradation which is necessary for its cellular activation is the principal target. Based on the quantity and diversity of data available on the biological activity of resveratrol, it has to be considered a very promising chemoprotector and chemotherapeutic. Urgent investigations on its bioavailability and effects on in vivo systems, especially in humans, are necessary.
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PMID:Resveratrol, a natural chemopreventive agent against degenerative diseases. 1198 29

Tumor necrosis factor (TNF), initially discovered as a result of its antitumor activity, has now been shown to mediate tumor initiation, promotion, and metastasis. In addition, dysregulation of TNF has been implicated in a wide variety of inflammatory diseases including rheumatoid arthritis, Crohn's disease, multiple sclerosis, psoriasis, scleroderma, atopic dermatitis, systemic lupus erythematosus, type II diabetes, atherosclerosis, myocardial infarction, osteoporosis, and autoimmune deficiency disease. TNF, however, is a critical component of effective immune surveillance and is required for proper proliferation and function of NK cells, T cells, B cells, macrophages, and dendritic cells. TNF activity can be blocked, either by using antibodies (Remicade and Humira) or soluble TNF receptor (Enbrel), for the symptoms of arthritis and Crohn's disease to be alleviated, but at the same time, such treatment increases the risk of infections, certain type of cancers, and cardiotoxicity. Thus blockers of TNF that are safe and yet efficacious are urgently needed. Some evidence suggests that while the transmembrane form of TNF has beneficial effects, soluble TNF mediates toxicity. In most cells, TNF mediates its effects through activation of caspases, NF-kappaB, AP-1, c-jun N-terminal kinase, p38 MAPK, and p44/p42 MAPK. Agents that can differentially regulate TNF expression or TNF signaling can be pharmacologically safe and effective therapeutics. Our laboratory has identified numerous such agents from natural sources. These are discussed further in detail.
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PMID:TNF blockade: an inflammatory issue. 1633 57

The incidence and mortality of prostate cancer (PCa) vary greatly in different geographic regions, for which lifestyle factors, such as dietary fat intake, have been implicated. Human 15-lipoxygenase-1 (h15-LO-1), which metabolizes polyunsaturated fatty acids, is a highly regulated, tissue-specific, lipid-peroxidating enzyme that functions in physiological membrane remodeling and in the pathogenesis of atherosclerosis, inflammation, and carcinogenesis. We have shown that aberrant overexpression of 15-LO-1 occurs in human PCa, particularly high-grade PCa, and in high-grade prostatic intraepithelial neoplasia (HGPIN), and that the murine orthologue is increased in SV40-based genetically engineered mouse (GEM) models of PCa, such as LADY and TRansgenic Adenocarcinoma of Mouse Prostate. To further define the role of 15-LO-1 in prostate carcinogenesis, we established a novel GEM model with targeted overexpression of h15-LO-1 in the prostate [human fifteen lipoxygenase-1 in mouse prostate (FLiMP)]. We used a Cre- mediated and a loxP-mediated recombination strategy to target h15-LO-1 specifically to the prostate of C57BL/6 mice. Wild-type (wt), FLiMP+/-, and FLiMP+/+ mice aged 7 to 21, 24 to 28, and 35 weeks were characterized by histopathology, immunohistochemistry (IHC), and DNA/RNA and enzyme analyses. Compared to wt mice, h15-LO-1 enzyme activity was increased similarly in both homozygous FLiMP+/+ and hemizygous FLiMP+/- prostates. Dorsolateral and ventral prostates of FLiMP mice showed focal and progressive epithelial hyperplasia with nuclear atypia, indicative of the definition of mouse prostatic intraepithelial neoplasia (mPIN) according to the National Cancer Institute. These foci showed increased proliferation by Ki-67 IHC. No progression to invasive PCa was noted up to 35 weeks. By IHC, h15-LO-1 expression was limited to luminal epithelial cells, with increased expression in mPIN foci (similar to human HGPIN). In summary, targeted overexpression of h15-LO-1 (a gene overexpressed in human PCa and HGPIN) to mouse prostate is sufficient to promote epithelial proliferation and mPIN development. These results support 15-LO-1 as having a role in prostate tumor initiation and as an early target for dietary or other prevention strategies. The FLiMP mouse model should also be useful in crosses with other GEM models to further define the combinations of molecular alterations necessary for PCa progression.
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PMID:Conditional expression of human 15-lipoxygenase-1 in mouse prostate induces prostatic intraepithelial neoplasia: the FLiMP mouse model. 1682 97

The Eph/ephrin system plays a vital role in diverse physiological events such as neurogenesis, vasculogenesis, and cell adhesion. Expression analysis of mRNA and protein in clinical samples revealed the involvement of the Eph/ephrin system in tumorigenesis, Alzheimer's disease, and atherosclerosis. Therefore, the Eph/ephrin system is considered a promising therapeutic target. However, no molecularly targeted drug against Ephs and ephrins is being used in the clinic thus far.Tumors are composed of various types of cells, including fibroblasts, immune cells, and endothelial cells. Recent studies showed the contribution of these cells to tumor growth, tumor progression, drug resistance, and metastasis. In this chapter, we discuss the role of Eph/ephrin system in the tumor microenvironment and describe its functions in tumor initiation, angiogenesis, cancer stem cell, tumor immunity, and also the metastatic environment.
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PMID:Eph/Ephrin Signaling in the Tumor Microenvironment. 3312 92