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)

Prostatic Intraepithelial Neoplasia (PIN) and prostatic cancer (PCA) are not caused by infection, allergic reaction, inadequate immunological response, ischemia, ageing, systemic hormones, carcinogens, nor prostatic ductal contents. PIN and PCA are apparently caused by increased inner acinar pressure due to partially blocked draining ducts. Only this explanation can account for all the observations about PIN and PCA. All other possible causes are disproved by specific observations. In order to further clarify the cause of PIN and PCA, it is important to discover if peripheral zone lesions cluster around ducts or blood vessels. PIN patterns are the morphological precursors of both PCA and prostatic cysts. Different PIN patterns represent different adaptive stages to increasing inner acinar pressure. The immediate tissue cause of PCA is PIN disruption seeding the stroma with high-grade PIN (HGPIN) cells. These cells, programmed for adaptive proliferation and mobility in PIN, are sufficient in the stroma to cause all stages and patterns of invasive PCA. No mutated cells are necessary. For reasons given, the primary cause of the initial ductal blockage that results in PIN and PCA cannot be inflammation, stones, proteineous plugs, infarction, venus thrombosis, ductal hyperplasia, nor a constricted penis at ejaculation. Only benign prostatic hyperplasia (BPH) can explain all the facts and is thus the primary cause of the ductal blockage resulting in cysts, PIN and PCA. The main causes of BPH are apparently disuse atrophy of sexual and abdominal muscles, and atherosclerosis of the capsular branch of the prostatic artery, causes atypical adenomatous hyperplasia (AAH) in the transition zone. The resulting muscular and glandular atrophy decreases local and general growth inhibitors. New growth in the adult prostate is abnormal because epithelial cells grow into ducts rather into the stroma. In such ducts, the growths cannot receive stromal growth inhibitory signals, and thus continue to grow indefinitely and result in BPH, AAH-adenosis, blockage of ducts, cysts, PIN and PCA.
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PMID:A unifying hypothesis that links benign prostatic hyperplasia and prostatic intraepithelial neoplasia with prostate cancer. Invited comments. 860 75

Prostatic atrophy (PA) is one of the most frequent mimics of prostatic adenocarcinoma. It occurs almost exclusively in the peripheral zone of the gland and gained importance with the increasing use of needle biopsies for the detection of prostatic carcinoma The etiopathogenesis is unknown, and there is controversy related to the potential of PA as a precancerous lesion. The frequency increases with age. Compressions caused by hyperplastic nodules, inflammation, hormones, nutritional deficiency, or systemic or local ischemia, are all possible factors in the pathogenesis of PA. The peripheral zone of the prostate was step-sectioned and totally embedded from the bodies of 100 consecutively autopsied men more than 40 years of age. The fragments were microscopically studied for presence of PA, latent (histologic) carcinoma, high-grade prostatic intraepithelial neoplasia, local arteriosclerosis, and prostatitis. The prostates were macroscopically examined for the presence of nodular prostatic hyperplasia. The autopsy reports provided information concerning the presence of generalized atherosclerosis and benign or malignant nephrosclerosis. PA was seen in 85 of the 100 prostates examined and histologically was subtyped into simple, hyperplastic, and sclerotic atrophy. In 65 (76.47%) of 85 cases, the histologic subtypes were combined. In 33 (50.76%) of these 65 cases, the three subtypes were seen concomitantly, favoring the hypothesis that they represent a morphologic continuum of only one lesion. Fibrosis of the stroma may or may not be present in simple and hyperplastic atrophy. Hyperplastic atrophy associated with fibrosis of the stroma is the histologic subtype that most frequently mimics adenocarcinoma Sclerotic atrophy always presents fibrosis of the stroma. PA increases with age, and, in our study, ischemia caused by local intense arteriosclerosis seems to be a potential factor for its etiopathogenesis. Because there was no relation to latent (histologic) carcinoma or high-grade prostatic intraepithelial neoplasia, PA is probably not a premalignant lesion.
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PMID:Prostatic atrophy: an autopsy study of a histologic mimic of adenocarcinoma. 955 22

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

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

Oxidative stress is known to be a key factor in many neurodegenerative diseases. Inflammation also plays a relevant role in a myriad of pathologies such as diabetes and atherosclerosis. Polyphenols coming from dietary sources, such as pterostilbene, may be beneficial in this type of diseases. However, most of them are rapidly metabolized and excreted, yielding very low phenolic bioavailability what makes it difficult to find out which are the mechanisms responsible for the observed bioactivity. Herein, we evaluate the effects of pterostilbene and its metabolites against H2O2-induced cell damage in human neuroblastoma SH-SY5Y cells and against lipopolysaccharide (LPS)-challenged RAW 264.7 macrophages. Among the metabolites tested, 3-methyl-4'-glucuronate-resveratrol (also called 4'-glucuronate pinostilbene, PIN-GlcAc, 11) prevented neuronal death via attenuation of reactive oxygen species (ROS) levels and increased REDOX activity in neurons. This compound is also able to ameliorate LPS-mediated inflammation on macrophages via inhibition of IL-6 and NO production. Thus, polyphenol from dietary sources could be part of potential functional foods designed to ameliorate the onset and progression of certain neurodegenerative diseases via oxidative stress reduction.
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PMID:Neuroprotective and Anti-inflammatory Effects of Pterostilbene Metabolites in Human Neuroblastoma SH-SY5Y and RAW 264.7 Macrophage Cells. 3195 26