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Vanillic acid attenuates testosterone-induced benign prostatic hyperplasia in rats and inhibits proliferation of prostatic epithelial cells.

ABSTRACT: Benign prostatic hyperplasia (BPH) is a common disease in the male population, especially in elderly men. Vanillic acid (VA), a dihydroxybenzoic derivative used as a flavoring agent, is reported to have an anti-inflammatory effect. However, there are no reports of its effects on BPH to date. BPH was induced with a pre-4-week treatment of daily subcutaneous injections of testosterone propionate (TP), and the normal control group received injections of ethanol with corn oil instead. Six weeks of further injections were done with (a) ethanol with corn oil, (b) TP only, (c) TP + finasteride, and (d) TP + VA. Finasteride was used as a positive control group. VA had protective effects on the TP-induced BPH. In the VA treatment group, the prostate weight was reduced, and the histological changes including the epithelial thickness and lumen area were restored like in the normal control group. Furthermore, in the VA treatment group, two proliferation related factors, high molecular weight cytokeratin 34?E12 and ? smooth muscle actin, were significantly down-regulated compared to the TP-induced BPH group. The expressions of dihydrotestosterone and 5?-reductase, the most crucial factors in BPH development, were suppressed by VA treatment. Expressions of the androgen receptor, estrogen receptor ? and steroid receptor coactivator 1 were also significantly inhibited by VA compared to the TP-induced BPH group. In addition, we established an in vitro model for BPH by treating a normal human prostatic epithelial cell line RWPE-1 with TP. VA successfully inhibited proliferation and BPH-related factors in a concentration-dependent manner in this newly established model. These results suggest a new and potential pharmaceutical therapy of VA in the treatment of BPH.

SUBMITTER: Jung Y

PROVIDER: S-EPMC5675626 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Vanillic acid attenuates testosterone-induced benign prostatic hyperplasia in rats and inhibits proliferation of prostatic epithelial cells.

Jung Yunu Y Park Jinbong J Kim Hye-Lin HL Youn Dong-Hyun DH Kang JongWook J Lim Seona S Jeong Mi-Young MY Sethi Gautam G Park Sung-Joo SJ Ahn Kwang Seok KS Um Jae-Young JY

Oncotarget 20170803 50

Benign prostatic hyperplasia (BPH) is a common disease in the male population, especially in elderly men. Vanillic acid (VA), a dihydroxybenzoic derivative used as a flavoring agent, is reported to have an anti-inflammatory effect. However, there are no reports of its effects on BPH to date. BPH was induced with a pre-4-week treatment of daily subcutaneous injections of testosterone propionate (TP), and the normal control group received injections of ethanol with corn oil instead. Six weeks of f ...[more]

PMID: 29152074

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Project description:Benign prostatic hyperplasia (BPH) is a serious illness affecting middle-aged and elderly male patients. It is a complication of several diseases including metabolic syndrome. BPH has been associated with inflammation and increased oxidative stress in prostatic tissues. Piceatannol (PIC) is an active natural polyhydroxylated stilbene found in many plants. It has profound anti-inflammatory as well as antioxidant activities. However, it suffers relatively poor pharmacokinetic properties. Nanoformulation is an acknowledged approach to improve PIC bioavailability. The goal was to evaluate the ability of PIC in preventing testosterone-induced benign prostatic hyperplasia in rats. PIC was prepared in a self-nanoemulsifying drug delivery system (SNEDDS). Animals were placed into seven groups: 1) control (vehicle), 2) PIC SNEDDS (20 mg/kg), 3) testosterone (3 mg/kg), 4) testosterone + PIC SNEDDS (5 mg/kg), 5) testosterone + PIC (10 mg/kg), 6) testosterone + PIC SNEDDS (20 mg/kg) and 7) testosterone + finasteride (5 mg/kg). Testosterone was injected SC while PIC SNEDDS and finasteride were given orally. All treatments were given once daily, 5 days/week for four consecutive weeks. PIC administration ameliorated increased prostate weights and indices in addition to histopathological alterations. Further it inhibited accumulation of lipid peroxidation, depletion of glutathione (GSH) and exhaustion of catalase (CAT). PIC SNEDDS exhibited anti-proliferative activities as demonstrated by the inhibition of cyclin D1 protein expression and Bcl2 mRNA expression in addition to enhancement of Bax mRNA expression and caspase-3 content. Immunohistochemically, PIC SNEDDS protected against the testosterone-induced increased expression of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), nuclear factor kappa B (NFκB) and also offered protection against the decline in Nrf2 expression. Further, a significant enhancement of Nfe212 and Homx1 mRNA expression was detected in PIC SNEDDS-treated animals in comparison to the testosterone group. Conclusively, PIC prepared in SNEDDS protects against experimentally induced BPH via modulation of, at least partly, Nrf2/HO-1/NFκB axis.

Project description:Background: Interleukins (ILs) and related chronic inflammation have been found to contribute to the development of benign prostatic hyperplasia (BPH) in recent decades. As a late member of the ILs family, IL-21 receptor (IL-21R) can modulate cell proliferation, however, IL-21R activity in the prostate has not been examined. The current study aimed to elucidate a potential role of IL-21R in the development of BPH. Material and Methods: Human prostate tissues, cell lines and rats were used. QRT-PCR, Western blot, and immunohistochemistry, along with hematoxylin and eosin, Masson's trichrome, and immunofluorescent staining were performed. BPH-1 cells with IL-21R silenced were cultured or co-cultured with macrophages (active THP-1, AcTHP-1). Apoptosis and cell cycle phases were determined via flow cytometry. Epithelial-mesenchymal transition (EMT) processes were also examined. In vivo, rat prostatitis was induced with intraprostatic injected lipopolysaccharide (LPS). Results: IL-21R was highly expressed in human as well as rat prostate, mainly in the epithelial compartment. BPH concomitant with prostatitis significantly upregulated the expression of IL-21R. Knockdown of IL-21R induced cell apoptosis and cycle arrest at G0/G1 phase, and blocked the EMT process in BPH-1 cells. When IL-21R silenced BPH-1 cells were co-cultured with AcTHP-1 cells, these aforementioned processes and IL-21R change were completely reversed. Prostatic hyperplasia was observed with IL-21R upregulated in LPS induced prostatitis rats. More specifically, the expression of apoptosis, cyclin, and EMT proteins in this rat model are altered in a manner consistent with that seen in the cell line model. Conclusions: Our novel data demonstrates the expression and functional activities of IL-21R in the mechanism for development of BPH. IL-21R mainly localized in prostate epithelium and it was upregulated in hyperplastic prostate tissues. IL-21R enhanced proliferation of BPH-1 cells, via inhibiting cell apoptosis, and modulating cell cycles, as well as the EMT process, in response to inflammatory stimuli.

Dataset Information

Vanillic acid attenuates testosterone-induced benign prostatic hyperplasia in rats and inhibits proliferation of prostatic epithelial cells.

Publications

Vanillic acid attenuates testosterone-induced benign prostatic hyperplasia in rats and inhibits proliferation of prostatic epithelial cells.

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