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Prostatic ischemia induces ventral prostatic hyperplasia in the SHR; possible mechanism of development of BPH.

ABSTRACT: In the light of increasing evidence that benign prostatic hyperplasia is associated with cardiovascular disease, we have investigated the relationship between prostatic blood flow and prostatic hyperplasia in the spontaneously-hypertensive-rat (SHR). Twelve-week-old male SHRs were treated with nicorandil for six weeks. Wistar-Kyoto rats were used as controls. Six weeks after nicorandil treatment, blood pressure and the prostatic blood flow were estimated, and tissue levels of malondialdehyde, HIF-1α, TGF-β1, bFGF, dihydrotestosterone, and α-SMA were measured. SHRs showed significant increases in blood pressure, tissue levels of malondialdehyde, HIF-1α, TGF-β1, bFGF, α-SMA and a significant decrease in the prostatic blood flow. Although treatment with nicorandil failed to alter the blood-pressure and α-SMA, it significantly ameliorated the increased levels of malondialdehyde, HIF-1α, TGF-β1, and bFGF. There were no significant differences in tissue levels of dihydrotestosterone among any groups. These data indicate that development of prostatic hyperplasia may be associated with prostatic hypoxia, which nicorandil prevents via its effect to increase the blood flow.

SUBMITTER: Saito M

PROVIDER: S-EPMC3897960 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Project description:Early studies suggested macrophages might play roles in inflammation-associated benign prostatic hyperplasia (BPH) development, yet the underlying mechanisms remain unclear. Here we first showed that CD68(+) macrophages were identified in both epithelium and the stromal area of human BPH tissues. We then established an in vitro co-culture model with prostate epithelial and macrophage cell lines to study the potential impacts of infiltrating macrophages in the BPH development and found that co-culturing prostate epithelial cells with macrophages promoted migration of macrophages. In a three-dimensional culture system, the sphere diameter of BPH-1 prostate cells was significantly increased during coculture with THP-1 macrophage cells. Mechanism dissection suggested that expression levels of epithelial-mesenchymal transition (EMT) markers, such as N-cadherin, Snail, and TGF-?2, were increased, and administration of anti-TGF-?2 neutralizing antibody during co-culture suppressed the EMT and THP-1-mediated growth of BPH-1 cells, suggesting THP-1 might go through EMT to influence the BPH development and progression. Importantly, we found that modulation of androgen receptor (AR) in BPH-1 and mPrE cells significantly increased THP-1 and RAW264.7 cell migration, respectively, and enhanced expression levels of EMT markers, suggesting that AR in prostate epithelial cells might play a role in promoting macrophage-mediated EMT in prostate epithelial cells. Silencing AR function via an AR degradation enhancer, ASC-J9, decreased the macrophage migration to BPH-1 cells and suppressed EMT marker expression. Together, these results provide the first evidence to demonstrate that prostate epithelial AR function is important for macrophage-mediated EMT and proliferation of prostate epithelial cells, which represents a previously unrecognized role of AR in the cross-talk between macrophages and prostate epithelial cells. These results may provide new insights for a new therapeutic approach to battle BPH via targeting AR and AR-mediated inflammatory signaling pathways.

Project description:ObjectiveTo explored the mechanism of Buzhong Yigi decoction ( BZYQD) in inhibiting prostatic cell proliferation effect.MethodsThe compounds of BZYQD consisted with eight herbs were searched in TCMSP databases and the putative targets of BZYQD were collected in Drugbank database. Then, "Benign prostatic hyperplasia" (BPH) was used to find the targets based on the GeneCards, Online Mendelian Inheritance in Man (OMIM) and Therapeutic Target Database (TTD) databases, and they were further used to collect further collect the intersection targets between BZYQD and BPH by counter-selection. Next, Herb-Compound-Target-Disease network was constructed by Cytoscape software and protein interaction network was built by Search tool for recurring instances of neighbouring genes (STRING) database. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were analyzed by Database for Annotation, Visualization and Integrated Discovery (DAVID) database to predict the mechanism of the intersection targets. Mitogen activated protein kinase 8 (MAPK8), interleukin 6 (IL-6) and quercetin were chosen to perform molecular docking. Then 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was to detect the bility of BPH-1 (BPH epithelial cell line) by treated with quercetin at the concentrations of 15, 30, 60, 120 μM for 12, 24, 48, 72 h. The production of IL-6, tumor necrosis factor-α (TNF-α), IL-1β and were mRNA expression detected by enzyme-linked immunosorbent assay kit and quantitative real-time polymerase chain reaction. Western blot was used to detect the expression of phospho-p38 mitogen-activated protein kinase (p-P38) and matrix metalloprotein-9 (MMP-9).ResultsA total 151 chemical ingredients of 8 herbs and 1756 targets in BZYQD, 105 common targets of BZYQD and BPH which mainly involving with MAPK8, IL-6, and so on. GO enrichment analysis got 352 GO entries (0.05) which included 208 entries of biological process, 64 entries of cell component and 80 entries of molecular function. KEGG pathway Enrichment analyses got 20 significant pathways which mainly involved with MAPK signaling way. MTT assay indicated quercetin inhibited the viability of BPH-1 cells by time-and dose-dependent manner. Quercetin decreased the IL-6, TNF-α and IL-1β production and mRNA expression, and the expression of p-P38 and MMP-9 were also obviously reduced after treated with quercetin.ConclusionsBZYQD inhibited BPH through suppressing inflammatory response which might involving with regulating the MAPK signaling way.

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Prostatic ischemia induces ventral prostatic hyperplasia in the SHR; possible mechanism of development of BPH.

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