Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phytoestrogens are naturally occurring plant-derived phytochemicals, whose common biological roles are to protect plants from stress or to act as part of a plant's defense mechanism. Although composed of a wide group of nonsteroidal compounds of diverse structure, phytoestrogens have been shown to bind estrogen receptors and to behave as weak agonist/antagonist in both animals and humans. Phytoestrogens include mainly isoflavones (IF), coumestans, and lignans. These compounds are known to be present in fruits, vegetables, and whole grains commonly consumed by humans. IF are found in legumes--mainly soybeans--whereas flaxseed is a major source of lignans, and coumestans are significantly present in clover, alfalfa and soybean sprouts. 8-Prenyl flavonoids are common in vegetables. Bioavailability of IF requires an initial hydrolysis of the sugar moiety by intestinal beta-glucosidases to allow the following uptake by enterocytes and the flow through the peripheral circulation. Following absorption, IF are then reconjugated mainly to glucuronic acid and to a lesser degree to sulphuric acid. Gut metabolism seems key to the determination of the potency of action. Several epidemiological studies correlated high dose consumptions of soy IF with multiple beneficial effects on breast and prostate cancers, menopausal symptoms, osteoporosis, atherosclerosis and stroke, and neurodegeneration. For the relief of menopausal symptoms a consumption of 60 mg aglycones/day has been suggested; for cancer prevention a consumption between 50 and 110 mg aglycones/day is considered beneficial to reduce risks of breast, colon and prostate cancer; to decrease cardiovascular risk a minimum intake of 40-60 mg aglycones/day, together with about 25 g of soy protein has been suggested. For improvement in bone mineral density, 60-100 mg aglycones/day for a period of at least 6-12 months could be beneficial.
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PMID:Health effects of phytoestrogens. 1570 93

Nuclear factor-kappaB (NF-kappaB) is a ubiquitous redox-sensitive transcription factor involved in the pro-inflammatory response to several factors, including cytokines and oxidative stress. Upon activation, NF-kappaB translocates into the nucleus and binds to specific nucleotide sequences. The cellular responses to inflammatory and stress signals have been implicated in disease conditions, such as atherosclerosis, cancer, diabetes, and Alzheimer's disease. The conventional method for detection of NF-kappaB -DNA binding activity is the electrophoretic mobility shift assay (EMSA), which is time-consuming and non-quantitative. Here, we report (a) development of a rapid, sensitive and quantitative chemiluminescent immunoassay (QCI) for analysis of NF-kappaB DNA-binding activity, and (b) validation of the QCI with the EMSA using nuclear and cytosolic extracts from cultured prostate cancer cells (PC3), rat liver homogenates and human lymphocytes. The QCI for analysis of NF-kappaB DNA binding activity has advantages over the EMSA: (1) Higher speed: 3-5h post sample preparation, (2) Greater sensitivity: 10pg NF-kappaB/well, (3) Quantitative: linear range: 10-1000pg NF-kappaB; r2 = 0.999 (4) High throughput adaptability: 96-well plate format can analyze up to 40 samples in duplicate, (5) SAFETY: No radioactive isotopes, (6) Simplicity, and (7) Capability of measurement of both activated (free) NF-KB which is translocated into the nucleus and total (bound + unbound) NF-kappaB present in the cytosol/cell.
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PMID:Quantitative chemiluminescent immunoassay for NF-kappaB-DNA binding activity. 1579 22

Despite nearly a half-century of research on aging and sex steroids in men, answers to key questions that would allow us to confidently assess risk:benefit ratios for androgen replacement in older men with the partial androgen deficiency of aging men (PADAM) syndrome remain uncertain. Although it is now reasonably clear that a significant percentage of otherwise healthy older men have decreases in testosterone and bioavailable testosterone to levels consistent with hypogonadism, the clinical implications of this change remain uncertain. Data suggest that low testosterone in older men is correlated to varying degrees with loss of lean body mass and muscle strength, and increased total and central body fat. Less certain, but suggestive, are data relating low testosterone levels to decreased bone density, loss of insulin sensitivity, and cognitive and affective deterioration, as well as reduced sexual function. Replacement of testosterone in older men has shown some positive effects on each of these variables, but findings have been inconsistent, perhaps because studies have employed different preparations and doses of androgens, treated for various durations, and defined their target populations in different ways. As important as beneficial effects is the potential for adverse effects, which may be greater in older men. Possible problems include sleep apnea, erythrocytosis, dyslipidemia with acceleration of atherosclerosis, and, of greatest concern, prostate cancer or hyperplasia. Studies to date have suggested that these outcomes are not major risks, but, in the absence of a large, randomized trial or trials, definitive information is not available. The US National Academies Institute of Medicine's recent report recommends that the National Institutes of Health support small efficacy trials aimed at treatment of androgen deficiency-related clinical conditions, but not a large, randomized trial to elucidate risk:benefit ratios. This recommendation, if adhered to, is likely to delay, rather than foster, progress in this important area.
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PMID:Testosterone in older men after the Institute of Medicine Report: where do we go from here? 1609 68

Disodium disuccinate astaxanthin ('rac'-dAST; Cardax) is a water-dispersible C40 carotenoid derivative under development for oral and parenteral administration for cardioprotection of the at-risk ischemic cardiovascular patient. In experimental infarction models in animals (rats, rabbits, and dogs), significant myocardial salvage has been obtained, up to 100% at the appropriate dose in dogs. The documented mechanism of action in vitro includes direct scavenging of biologically produced superoxide anion; in vivo in rabbits, modulation of the complement activity of serum has also been shown. A direct correlation between administration of the test compound in animals and reductions of multiple, independent markers of oxidative stress in serum was recently obtained in a rat experimental infarction model. For the current study, it was hypothesized that oral Cardax administration would inhibit oxidative damage of multiple relevant biological targets in a representative, well-characterized murine peritoneal inflammation model. A previously developed mass spectrometry-based (LC/ESI/MS/MS) approach was used to interrogate multiple distinct pathways of oxidation in a black mouse (C57/BL6) model system. In vivo markers of oxidant stress from peritoneal lavage samples (supernatants) were evaluated in mice on day eight (8) after treatment with either Cardax or vehicle (lipophilic emulsion without drug) orally by gavage at 500 mg/kg once per day for seven (7) days at five (5) time points: (1) baseline prior to treatment (t=0); (2) 16 h following intraperitoneal (i.p.) injection with thioglycollate to elicit a neutrophilic infiltrate; (3) 4 h following i.p. injection of yeast cell wall (zymosan; t=16 h/4 h thioglycollate+zymosan); (4) 72 h following i.p. injection with thioglycollate to elicit monocyte/macrophage infiltration; and (5) 72 h/4 h thioglycollate+zymosan. A statistically significant sparing effect on the arachidonic acid (AA) and linoleic acid (LA) substrates was observed at time points two and five. When normalized to the concentration of the oxidative substrates, statistically significant reductions of 8-isoprostane-F(2alpha) (8-iso-F(2alpha)) at time point three (maximal neutrophil recruitment/activation), and 5-HETE, 5-oxo-EET, 11-HETE, 9-HODE, and PGF(2alpha) at time point five (maximal monocyte/macrophage recruitment/activation) were observed. Subsequently, the direct interaction of the optically inactive stereoisomer of Cardax (meso-dAST) with human 5-lipoxygenase (5-LOX) was evaluated in vitro with circular dichroism (CD) and electronic absorption (UV/Vis) spectroscopy, and subsequent molecular docking calculations were made using mammalian 15-LOX as a surrogate (for which XRC data has been reported). The results suggested that the meso-compound was capable of interaction with, and binding to, the solvent-exposed surface of the enzyme. These preliminary studies provide the foundation for more detailed evaluation of the therapeutic effects of this compound on the 5-LOX enzyme, important in chronic diseases such as atherosclerosis, asthma, and prostate cancer in humans.
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PMID:The effects of oral Cardax (disodium disuccinate astaxanthin) on multiple independent oxidative stress markers in a mouse peritoneal inflammation model: influence on 5-lipoxygenase in vitro and in vivo. 1646 47

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

Diabetes is associated with reduced risk of prostate cancer, but whether the metabolic syndrome is associated with prostate cancer is not established. The authors assessed this association in the Atherosclerosis Risk in Communities (ARIC) Study, comprising 6,429 men in four US communities initially with no history of cancer and aged 45-64 years. Metabolic syndrome and other risk factors were assessed in 1987-1989. Follow-up for prostate cancer incidence (n = 385 through 2000) was accomplished through cancer registry and hospital linkage. At baseline, 1,871 men (29.5%) had the metabolic syndrome. After the authors adjusted for other risk factors, men with the metabolic syndrome (> or =3 components) were significantly less likely to develop prostate cancer (relative risk = 0.77, 95% confidence interval: 0.60, 0.98) than men without the metabolic syndrome. Diabetes was negatively associated with prostate cancer, although the confidence interval included 1 (relative risk = 0.73, 95% confidence interval: 0.51, 1.05). When diabetic participants were excluded, the inverse association between metabolic syndrome and prostate cancer incidence was slightly strengthened. In this study, the metabolic syndrome was associated with decreased prostate cancer incidence. The authors hypothesize that this finding reflects a decrease in bioavailable (free and albumin-bound) testosterone with the metabolic syndrome and a concomitant reduction in prostate cancer risk.
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PMID:The metabolic syndrome is associated with reduced risk of prostate cancer. 1696 59

Fifteen (15)-lipoxygenase type 1 (15-LO-1, ALOX15), a highly regulated, tissue- and cell-type-specific lipid-peroxidating enzyme has several functions ranging from physiological membrane remodeling, pathogenesis of atherosclerosis, inflammation and carcinogenesis. Several of our findings support a possible role for 15-LO-1 in prostate cancer (PCa) tumorigenesis. In the present study, we identified a CpG island in the 15-LO-1 promoter and demonstrate that the methylation status of a specific CpG within this island region is associated with transcriptional activation or repression of the 15-LO-1 gene. High levels of 15-LO-1 expression was exclusively correlated with one of the CpG dinucleotides within the 15-LO-1 promoter in all examined PCa cell-lines expressing 15-LO-1 mRNA. We examined the methylation status of this specific CpG in microdissected high grade prostatic intraepithelial neoplasia (HGPIN), PCa, metastatic human prostate tissues, normal prostate cell lines and human donor (normal) prostates. Methylation of this CpG correlated with HGPIN, PCa and metastatic human prostate tissues, while this CpG was unmethylated in all of the normal prostate cell lines and human donor (normal) prostates that either did not display or had minimal basal 15-LO-1 expression. Immunohistochemistry for 15-LO-1 was performed in prostates from PCa patients with Gleason scores 6, 7 [(4+3) and (3+4)], >7 with metastasis, (8-10) and 5 normal (donor) individual males. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect 15-LO-1 in PrEC, RWPE-1, BPH-1, DU-145, LAPC-4, LNCaP, MDAPCa2b and PC-3 cell lines. The specific methylated CpG dinucleotide within the CpG island of the 15-LO-1 promoter was identified by bisulfite sequencing from these cell lines. The methylation status was determined by COBRA analyses of one specific CpG dinucleotide within the 15-LO-1 promoter in these cell lines and in prostates from patients and normal individuals. Fifteen-LO-1, GSTPi and beta-actin mRNA expression in BPH-1, LNCaP and MDAPCa2b cell lines with or without 5-aza-2'-deoxycytidine (5-aza-dC) and trichostatin-A (TSA) treatment were investigated by qRT-PCR. Complete or partial methylation of 15-LO-1 promoter was observed in all PCa patients but the normal donor prostates showed significantly less or no methylation. Exposure of LNCAP and MDAPCa2b cell lines to 5-aza-dC and TSA resulted in the downregulation of 15-LO-1 gene expression. Our results demonstrate that 15-LO-1 promoter methylation is frequently present in PCa patients and identify a new role for epigenetic phenomenon in PCa wherein hypermethylation of the 15-LO-1 promoter leads to the upregulation of 15-LO-1 expression and enzyme activity contributes to PCa initiation and progression.
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PMID:DNA methylation paradigm shift: 15-lipoxygenase-1 upregulation in prostatic intraepithelial neoplasia and prostate cancer by atypical promoter hypermethylation. 1716 46

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

Age-related decline in serum testosterone and dehydroepiandrosterone sulfate concentrations occur in men. Low concentrations of these endogenous androgens have been linked with insulin resistance, which is an important upstream driver for metabolic abnormalities such as hyperglycemia, hypertension, or hyperlipidemia, and increased cardiovascular risk. Moreover, men with diabetes have significantly less circulating androgen than nondiabetic men. Here, we summarize how androgen affects insulin resistance and atherosclerosis in men with type 2 diabetes. Low serum concentrations of endogenous androgens are associated with visceral fat accumulation. Androgen deprivation by castration to treat prostate cancer increases insulin resistance, while testosterone administration in type 2 diabetic men with androgen deficiency improves glucose homeostasis and decreases visceral fat, in addition to alleviating symptoms of androgen deficiency including erectile dysfunction. Androgen correlates inversely with severity of atherosclerosis and has beneficial effects upon vascular reactivity, inflammatory cytokine, adhesion molecules, insulin resistance, serum lipids, and hemostatic factors. Because men with type 2 diabetes have relative hypogonadism, testosterone supplementation could decrease both insulin resistance and atherosclerosis.
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PMID:Role of endogenous androgen against insulin resistance and athero- sclerosis in men with type 2 diabetes. 1822 Jun 53

More than 30 Curcuma species (Zingiberaceae) are found in Asia, where the rhizomes of these plants are used as both food and medicine, such as in traditional Chinese medicine. The plants are usually aromatic and carminative, and are used to treat indigestion, hepatitis, jaundice, diabetes, atherosclerosis and bacterial infections. Among the Curcuma species, C. longa, C. aromatica and C. xanthorrhiza are popular. The main constituents of Curcuma species are curcuminoids and bisabolane-type sesquiterpenes. Curcumin is the most important constituent among natural curcuminoids found in these plants. Published research has described the biological effects and chemistry of curcumin. Curcumin derivatives have been evaluated for bioactivity and structure-activity relationships (SAR). In this article, we review the literature between 1976 and mid-2008 on the anti-inflammatory, anti-oxidant, anti-HIV, chemopreventive and anti-prostate cancer effects of curcuminoids. Recent studies on curcuminoids, particularly on curcumin, have discovered not only much on the therapeutic activities, but also on mechanisms of molecular biological action and major genomic effects.
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PMID:Recent advances in the investigation of curcuminoids. 1879 84


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