Mechanistic investigation of the adrenergic induction of ventral prostate hyperplasia in mice

Marinese, Dorene; Patel, Rahila; Walden, Paul D.

doi:10.1002/pros.10170

Cited by 48 publications

(40 citation statements)

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“…28) In our study, TP injection significantly increased the level of serum testosterone, and that finasteride and QI partially reversed this effect (Fig. 3A).…”

Section: Effect Of Qi On the Viability Of Human Prostate Cancer Cellssupporting

confidence: 67%

<i>Quisqualis indica</i> Improves Benign Prostatic Hyperplasia by Regulating Prostate Cell Proliferation and Apoptosis

Wijerathne

Park

Jeong

et al. 2017

Biological & Pharmaceutical Bulletin

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Quisqualis indica (QI) has been used for treating disorders such as stomach pain, constipation, and digestion problem. This study was aimed to evaluate the therapeutic efficacy of QI extract on treating benign prostatic hyperplasia (BPH) in LNCaP human prostate cancer cell line and a testosterone-induced BPH rat model. LNCaP cells were treated with QI plus testosterone propionate (TP), and androgen receptor (AR) and prostate specific antigen (PSA) expression levels were assessed by Western blotting. To induce BPH, the rats were subjected to a daily subcutaneous injection of TP (3 mg/kg) for 4 weeks. The rats in treatment group were orally gavaged with QI (150 mg/kg) together with the TP injection. In-vitro studies showed that TPinduced increases in AR and PSA expression in LNCaP cells were reduced by QI treatment. In BPH-model rats, the prostate weight, testosterone in serum, dihydrotestosterone (DHT) concentration and 5α-reductase type 2 mRNA expression in prostate tissue were significantly reduced following the treatment with QI. TPinduced prostatic hyperplasia and the expression of proliferating cell nuclear antigen (PCNA) and cyclin D1 were significantly attenuated in QI-treated rats. In addition, QI induced apoptosis by up-regulating caspase-3 and -9 activity and decreasing the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) ratio in prostate tissues of BPH rats. Further investigation showed that TP-induced activation of AKT and glycogen synthase kinase 3β (GSK3β) was reduced by QI administration. Therefore, our findings suggest that QI attenuates the BPH state in rats through anti-proliferative and pro-apoptotic activities and might be useful in the clinical treatment of BPH.Key words benign prostatic hyperplasia; dihydrotestosterone; Quisqualis indica; testosterone Benign prostatic hyperplasia (BPH) is a common urogenital disorder that affects up to 85% of males who are over 50 years-old. 1) BPH is characterized by the increased proliferation of epithelial and stromal cells of the prostate.2) BPH generally causes lower urinary tract symptoms (LUTS), such as incomplete bladder emptying, bladder obstruction, bloody urination, and frequent urination.3)The etiology of BPH is not entirely clear. However, the development and incidence of BPH are associated with dysregulation of androgens, and with increased proliferation and decreased apoptosis of cells in the prostate gland.4-9) Testosterone and dihydrotestosterone (DHT) have key roles in the development and growth of the entire male genital tract, and they stimulate differentiation of the prostate gland. 10,11) The adrenal glands and testes synthesize testosterone, and prostatic 5α-reductase type 2 converts it to DHT. 12) DHT then binds to the androgen receptor (AR), which is transported to the nucleus, where it regulates genes important for prostate growth and differentiation. 4) BPH development and progression are associated with activation of the AKT pathway, a major growth factor-mediated signal transduction pathways. 6)Over-stimulation of the ...

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“…28) In our study, TP injection significantly increased the level of serum testosterone, and that finasteride and QI partially reversed this effect (Fig. 3A).…”

Section: Effect Of Qi On the Viability Of Human Prostate Cancer Cellssupporting

confidence: 67%

<i>Quisqualis indica</i> Improves Benign Prostatic Hyperplasia by Regulating Prostate Cell Proliferation and Apoptosis

Wijerathne

Park

Jeong

et al. 2017

Biological & Pharmaceutical Bulletin

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“…Most rodents and nonhuman primates do not spontaneously develop BPH. Models for BPH are limited to rats and dogs, but they do not mimic all aspects of the human disease (28,29).…”

Section: Discussionmentioning

confidence: 99%

Stromal growth and epithelial cell proliferation in ventral prostates of liver X receptor knockout mice

Kim

Andersson

Bouton

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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With specific liver X receptor ␣ and ␤ (LXR␣ and LXR␤) antibodies, we found that LXR␣ is strongly expressed in the luminal and basal cells of prostatic epithelium. The ventral prostates (VP) of LXR␣ ؊/؊ mice are characterized by the presence of smooth-muscle actinpositive stromal overgrowth around the prostatic ducts and by numerous fibrous nodules pushing into the ducts and causing obstruction, so that most of the ducts were extremely dilated. BrdU labeling and Ki67 staining revealed epithelial and stromal proliferation in the fibrous nodules. However, the dense stroma surrounding the ducts was not positive for proliferation markers. There was no detectable difference between WT and LXR␣ ؊/؊ mice VP in the expression of the androgen receptor, but there was an increase in nuclear expression of Snail and Smad 2/3, indicating enhanced TGF-␤ signaling. Upon treatment of WT mice for 3 months with the LXR agonist T2320 or for 3 weeks with ␤-sitosterol, LXR␣ was downregulated, and a VP phenotype similar to that of LXR␣ ؊/؊ mice resulted. We conclude that in rodents, LXR␣ seems to control VP stromal growth and that LXR␣ ؊/؊ mice may be a useful model to study prostatic stromal hyperplasia. Because LXR␣ is expressed in the epithelium, the excessive stromal growth in LXR␣ ؊/؊ mice indicates that LXR␣ is essential for epithelial stromal communication.Benign prostatic hyperplasia ͉ liver X receptor ͉ TGF-␤ ͉ mesenchymal transformation ͉ snail L iver X receptor ␣ and ␤ (LXR␣ and LXR␤) are members of the nuclear receptor supergene family of ligandactivated transcription factors (1-3). LXR␣ and -␤ knockout mice have revealed that LXR␣ but not LXR␤ plays an important role in cholesterol homeostasis, whereas LXR␤ has key functions in the immune system, testis, adrenal gland, pancreas, and CNS (4 -12). The endogenous ligands of LXR are oxysterols (13, 14), but they also accept phytosterols, particularly ␤-sitosterol, as ligands (15). Because ␤-sitosterol is thought to be the active ingredient in the over-the-counter preparation used for relief of the symptoms of benign prostatic hyperplasia (BPH) (16), we investigated the role of LXR in the prostate and the possibility that the beneficial effects of ␤-sitosterol are mediated by LXR (17).BPH is a very common disorder in men aged 50 years and is characterized by lower urinary tract disorders that have severe effects on quality of life (18)(19)(20)(21). One of the current theories for the mechanism of BPH is that autocrine and paracrine signaling from stromal cells to epithelium creates a focal area of reawakening of epithelial budding and BPH nodule formation (22). The signaling molecules most commonly implicated in the etiology of BPH are TGF-␤, FGF, EGF, and insulin-like growth factor (22). Current surgical treatments are associated with risk of urinary incontinence, and current pharmacologic intervention is not always effective. Many men try phytotherapy (use of plants and herbs) for relief of the symptoms of BPH. The most popular phytotherapy is ␤-sitosterol and saw palmetto (...

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mentioning

confidence: 99%

“…[4][5][6] Administration of the sympathomimetic phenylephrine induces ventral prostate hyperplasia associated with reduced rates of cellular apoptosis, but not with increased rates of cellular proliferation. 7 Moreover, rapid proliferation of prostatic epithelial cells has been seen in the spontaneously hypertensive rat, 8 an animal model with in-creased prostatic norepinephrine levels. 9 Autonomic innervation is also implicated in the differentiation of stromal cells; norepinephrine stimulation directly modulates BPH-derived prostatic stromal cells towards a differential smooth muscle phenotype, 10 while treatment of cell cultures with doxazosin, an 1-ADR antagonist, inhibits this procedure.…”

mentioning

confidence: 99%

Terazosin treatment suppresses basic fibroblast growth factor expression in the rat ventral prostate

Mitropoulos

Kyroudi-Voulgari²,

Christelli³

et al. 2009

CIM

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Purpose: Alpha1-adrenergic receptor antagonists may not act solely on smooth muscle contractility. We evaluated the in vivo effect of the alpha1 blocker, terazosin, on the expression of basic fibroblast growth factor (bFGF) in the rat ventral prostate. Methods: Wistar rats were treated with terazosin (1.2 mg/ kg body weight, po, every second day) for 120 days. The expression of bFGF was assessed immuno-histochemically in tissue sections and by Western blotting in whole tissue preparations. Results: Terazosin treatment did not affect prostate weight or histomorphology. In the control group, epithelial and stromal cells demonstrated positive staining for the antibFGF antibody. In contrast, the same staining in terazosintreated specimens was either absent or extremely weak. An analogous difference was observed among the corresponding immunoblots. Conclusions: These findings implicate the reduction of bFGF expression by terazosin as a potential additional molecular mechanism of its action that may include alterations in peptide growth factor mediated prostate homeostasis.Drugs that block the action of sympathetic neurotransmitters on 1-adrenergic receptors ( 1-ADRs) are widely used for the treatment of patients with benign prostate hyperplasia (BPH)-related lower urinary tract symptoms. The rationale for their use stems is that they effectively relax prostate smooth muscles, 1 which represent approximately 40% of the cellular volume in hyperplastic glands. 2 The biological effects of extrinsic factors such as hormones and other endocrine-related agents on the prostate are mediated by various peptide growth factors produced by the gland and influence prostate growth, differentiation and function by promoting inter-and intracellular signaling between and within cell populations, through paracrine, autocrine and intracrine effects. 3 Data from several studies indicate that 1-ADR antagonists may not act solely on smooth muscle contractility. Intact autonomic innervation of the rat ventral prostate is necessary to maintain its structural and functional integrity. [4][5][6] Administration of the sympathomimetic phenylephrine induces ventral prostate hyperplasia associated with reduced rates of cellular apoptosis, but not with increased rates of cellular proliferation. 7 Moreover, rapid proliferation of prostatic epithelial cells has been seen in the spontaneously hypertensive rat, 8 an animal model with in-ORIGINAL RESEARCH

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Mechanistic investigation of the adrenergic induction of ventral prostate hyperplasia in mice

Cited by 48 publications

References 24 publications

<i>Quisqualis indica</i> Improves Benign Prostatic Hyperplasia by Regulating Prostate Cell Proliferation and Apoptosis

<i>Quisqualis indica</i> Improves Benign Prostatic Hyperplasia by Regulating Prostate Cell Proliferation and Apoptosis

Stromal growth and epithelial cell proliferation in ventral prostates of liver X receptor knockout mice

Terazosin treatment suppresses basic fibroblast growth factor expression in the rat ventral prostate

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