Search Results (28)

Background/Objectives: This study is the first report on isolating a natural benzyl benzoate (nBB) from Acridocarpus smeathmannii (DC.) Guill. & Perr roots. Methods: The structure was verified using GC-MS, HPLC-UV-VIS, and two-dimensional NMR. Since it is known for its vasodilatory and anti-spasmolytic actions, we investigated the biological effects of nBB on human prostate smooth tissue (rPx) obtained from a radical prostatectomy. For this purpose, rPx was incubated with nBB (0.05, 0.25, or 0.5 µM) in an organ bath, and then cumulative concentration–response curves were constructed for adrenergic agonists and electrical field stimulation (EFS). Results: Adding the various concentrations, nBB showed potential inhibition during agonist-induced contractions (0.1–100 µM). Also, neurogenic contractions of rPx by EFS (2–32 Hz) were reduced by up to 57%. Conclusions: Overall, this study reports on an efficient protocol of nBB isolation from A. smeathmannii and its contractility effects on human prostate smooth muscle. Potentially, this could contribute to the natural production of BB from A. smeathmannii species while giving it evolutionary recognition. However, since BB influences prostate smooth muscle contractility, caution in patients taking herbal supplements containing nBB is essential, as this may play a role in contributing to the symptoms of urinary tract conditions. Full article

Background: Lower urinary tract symptoms (LUTS) due to prostate hyperplasia are the most frequent urological symptoms in elderly men. Current pharmacological treatments for LUTS and benign prostatic hyperplasia (BPH) are widely used in clinical practice; however, adverse effects associated with these drugs have been reported for sexual dysfunction and orthostatic hypotension. Prunella vulgaris (PV) is a medicinal herb that has a long history of use. This study aimed to address this gap by investigating the relaxant activity of PV extract (PVE) on rat prostate smooth muscle ex vivo and evaluating intravesical cystometry for its potential. Methods and Results: Ten male Sprague Dawley (SD) rats were used to study the relaxant efficacy of PVE and its constituents in isometric contraction ex vivo. Thirty-six SD rats were randomly assigned to six groups of six animals (n = 6) and administered testosterone propionate (TP; 3 mg/kg) daily for 4 weeks to induce BPH. Groups of BPH rats were treated with or without PVE (30, 60, or 90 mg/kg) via oral gavage. At the end of the experiments, the animals were subjected to intravesical pressure under urethane anesthesia. After successful cystometric recording, rats were euthanized with carbon dioxide. Prostate and bladder tissues were harvested and processed for histological and biochemical analysis. The results demonstrated that PVE exerted relaxant effects on prostatic smooth muscle in a concentration-dependent manner, mediated by nitric oxide and potassium channels, without antagonizing adrenergic receptors. Additionally, intravesical cystometry in SD rats treated with oral gavage of PVE for 4 weeks showed a significant improvement in voiding abnormalities. Conclusions: These findings suggest the potential of PV and its compounds as a therapeutic strategy to improve LUTS associated with BPH. Full article

Hydrogen sulfide (H₂S), previously regarded as a toxic exhaust and atmospheric pollutant, has emerged as the third gaseous signaling molecule following nitric oxide (NO) and carbon monoxide (CO). Recent research has revealed significant biological effects of H₂S in a variety of systems, such as the nervous, cardiovascular, and digestive systems. Additionally, H₂S has been found to impact reproductive system function and may have therapeutic implications for reproductive disorders. This paper explores the relationship between H₂S and male reproductive disorders, specifically erectile dysfunction, prostate cancer, male infertility, and testicular damage. Additionally, it examines the impact of H₂S regulation on the pathophysiology of the female reproductive system, including improvements in preterm birth, endometriosis, pre-eclampsia, fetal growth restriction, unexplained recurrent spontaneous abortion, placental oxidative damage, embryo implantation, recovery of myometrium post-delivery, and ovulation. The study delves into the regulatory functions of H₂S within the reproductive systems of both genders, including its impact on the NO/cGMP pathway, the activation of K⁺ channels, and the relaxation mechanism of the spongy smooth muscle through the ROCK pathway, aiming to broaden the scope of potential therapeutic strategies for treating reproductive system disorders in clinical settings. Full article

Introduction: Benign prostatic hyperplasia (BPH) is a common pathologic process in aging men, and the contraction of the prostatic smooth muscles (SMs) in the stroma plays a vital role in this pathogenesis, leading to lower urinary tract symptoms (LUTSs). The isoforms of both the SM myosin (SMM) and non-muscle myosin (NMM) are associated with the contraction type of the prostatic SMs, but the mechanism has not been fully elucidated. Methods: We collected prostate tissues from 30 BPH patients receiving surgical treatments, and normal human prostate samples were obtained from 12 brain-dead men. A testosterone-induced (T-induced) rat model was built, and the epithelial hyperplastic prostates were harvested. Competitive RT-PCR was used to detect the expression of SMM isoforms. We investigated the contractility of human prostate strips in vitro in an organ bath. Results: The results regarding the comparisons of SMM isoforms varied between rat models and human samples. In comparison with T-induced rats and controls, competitive RT-PCR failed to show any statistically significant difference regarding the compositions of SMM isoforms. For human prostates samples, BPH patients expressed more SM-1 isoforms (66.8% vs. 60.0%, p < 0.001) and myosin light chain-17b (MLC_17b) (35.9% vs. 28.5%, p < 0.05) when compared to young donors. There was a significant decrease in prostate myosin heavy chain (MHC) expression in BPH patients, with a 66.4% decrease in MHC at the mRNA level and a 51.2% decrease at the protein level. The upregulated expression of non-muscle myosin heavy chain-B (NMMHC-B) was 1.6-fold at the mRNA level and 2.1-fold at the protein level. The organ bath study showed that isolated prostate strips from BPH patients produced slower tonic contraction compared to normal humans. Conclusion: In this study, we claim that in the enlarged prostates of patients undergoing surgeries, MHC expression significantly decreased compared to normal tissues, with elevated levels of SM-1, MLC_17b, and NMMHC-B isoforms. Modifications in SMM and NMM might play a role in the tonic contractile properties of prostatic SMs and the development of LUTS/BPH. Understanding this mechanism might provide insights into the origins of LUTS/BPH and facilitate the identification of novel therapeutic targets. Full article

Lysophosphatidic acid (LPA) is a lipid mediator that binds to G-protein-coupled receptors, eliciting a wide variety of responses in mammalian cells. Lyso-phospholipids generated via phospholipase A₂ (PLA₂) can be converted to LPA by a lysophospholipase D (lyso-PLD). Secreted lyso-PLDs have been studied in more detail than membrane-localized lyso-PLDs. This study utilized in vitro enzyme assays with fluorescent substrates to examine LPA generation in membranes from multiple mammalian cell lines (PC12, rat pheochromocytoma; A7r5, rat vascular smooth muscle; Rat-1, rat fibroblast; PC-3, human prostate carcinoma; and SKOV-3 and OVCAR-3, human ovarian carcinoma). The results show that membranes contain a lyso-PLD activity that generates LPA from a fluorescent alkyl-lyso-phosphatidylcholine, as well as from naturally occurring acyl-linked lysophospholipids. Membrane lyso-PLD and PLD activities were distinguished by multiple criteria, including lack of effect of PLD2 over-expression on lyso-PLD activity and differential sensitivities to vanadate (PLD inhibitor) and iodate (lyso-PLD inhibitor). Based on several lines of evidence, including siRNA knockdown, membrane lyso-PLD is distinct from autotaxin, a secreted lyso-PLD. PC-3 cells express GDE4 and GDE7, recently described lyso-PLDs that localize to membranes. These findings demonstrate that membrane-associated lyso-D activity, expressed by multiple mammalian cell lines, can contribute to LPA production. Full article

A recent in vivo study in pigs demonstrated the hypotensive properties of essential oil extracted from the blossoming plant Elsholtzia ciliata. This study was designed to examine the effect of E. ciliata essential oil (EO) on smooth muscle contraction. Tension measurements were performed on prostate strips and intact aortic rings isolated from rats. Results showed that EO caused a concentration-dependent reduction in phenylephrine-induced contraction of both the prostate and aorta, with a more pronounced inhibitory effect in the prostate. The IC₅₀ of EO for the prostate was 0.24 ± 0.03 µL/mL (n = 10) and for the aorta was 0.72 ± 0.11 µL/mL (n = 4, p < 0.05 vs. prostate). The chromatographic analysis identified elsholtzia ketone (10.64%) and dehydroelsholtzia ketone (86.23%) as the predominant compounds in the tested EO. Since both compounds feature a furan ring within their molecular structure, other furan ring-containing compounds, 2-acetylfuran (2AF) and 5-methylfurfural (5MFF), were examined. For the first time, our study demonstrated the relaxant effects of 2AF and 5MFF on smooth muscles. Further, results showed that EO, 2AF, and 5MFF altered the responsiveness of prostate smooth muscle cells to phenylephrine. Under control conditions, the EC50 of phenylephrine was 0.18 ± 0.03 µM (n = 5), while in the presence of EO, 2AF, or 5MFF, the EC50 values were 0.81 ± 0.3 µM (n = 5), 0.89 ± 0.11 µM (n = 5), and 0.69 ± 0.23 µM (n = 4), respectively, p < 0.05 vs. control. Analysis of the affinity of EO for α₁-adrenergic receptors in the prostate suggested that EO at a certain range of concentrations has a competitive antagonistic effect on α₁-adrenergic receptors. In conclusion, EO elicits a relaxant effect on smooth muscles which may be related to the inhibition of α₁-adrenoreceptors. Full article

Polychlorinated biphenyls (PCBs) are persistent organic pollutants linked to deleterious health outcomes, including voiding dysfunction in developmentally exposed mice. Changes in prostate volume and/or extracellular matrix composition are associated with voiding dysfunction in men and animal models. Whether PCB-induced changes in voiding function in male mice occur in part via alterations to the prostate or an alternate mechanism is unclear. Therefore, we tested whether developmental exposure to the MARBLES PCB mixture altered prostate morphology in young adult offspring. C57Bl/6J female mice were dosed daily with the MARBLES PCB mixture at 0, 0.1, 1 or 6 mg/kg/d for two weeks prior to mating and through gestation and lactation, offspring were collected at 6 weeks of age. Ventral prostate mass was decreased in the 1 mg/kg/d PCB group compared to other PCB groups. There were no PCB-induced changes in prostate smooth muscle thickness, apoptosis, proliferation, or testes mass. PCBs impacted the prostate extracellular matrix; anterior prostate collagen density was decreased in the 1 mg/kg/d PCB group compared to all other groups. Normalized bladder volume was increased in male and female offspring in the 6 mg/kg/d PCB group compared to control. No change in water consumption, bladder mass or bladder smooth muscle thickness accompanied changes in bladder volume. Urine and serum creatinine concentrations were elevated but only in male mice. Together, these results suggest that developmental exposure to PCBs can influence prostate wet weight and prostate/bladder morphology, but PCBs do not promote prostate enlargement. Whether these changes persist throughout adult life and how they contribute to voiding function in animal models and humans is of future interest. Full article

A dynamic interplay between prostate cancer (PCa) cells and reactive bone stroma modulates the growth of metastases within the bone microenvironment. Of the stromal cells, metastasis-associated fibroblasts (MAFs) are known to contribute but are the least studied cell type in PCa tumour progression. It is the aim of the current study to establish a biologically relevant 3D in vitro model that mimics the cellular and molecular profiles of MAFs found in vivo. Using 3D in vitro cell culture models, the bone-derived fibroblast cell line, HS-5, was treated with conditioned media from metastatic-derived PCa cell lines, PC3 and MDA-PCa 2b, or mouse-derived fibroblasts 3T3. Two corresponding reactive cell lines were propagated: HS5-PC3 and HS5-MDA, and evaluated for alterations in morphology, phenotype, cellular behaviour, plus protein and genomic profiles. HS5-PC3 and HS5-MDA displayed distinct alterations in expression levels of N-Cadherin, non-functional E-Cadherin, alpha-smooth muscle actin (α-SMA), Tenascin C, and vimentin, along with transforming growth factor receptor expression (TGF β R1 and R2), consistent with subpopulations of MAFs reported in vivo. Transcriptomic analysis revealed a reversion of HS5-PC3 towards a metastatic phenotype with an upregulation in pathways known to regulate cancer invasion, proliferation, and angiogenesis. The exploitation of these engineered 3D models could help further unravel the novel biology regulating metastatic growth and the role fibroblasts play in the colonisation process. Full article

Erectile dysfunction (ED) is a common and feared complication of radical prostatectomy (RP) for prostate cancer. Recently, tissue engineering for post-prostatectomy ED has been attempted in which controlled interactions between cells, growth factors, and the extracellular matrix (ECM) are important for the structural integrity if nerve regeneration. In this study, we evaluated the effects of a biomechanical ECM patch on the morphology and behavior of human bone marrow-derived mesenchymal stem cells (hBMSCs) in a bilateral cavernous nerve injury (BCNI) rat model. The ECM patch, made of decellularized human fibroblast-derived ECM (hFDM) and a biocompatible polyvinyl alcohol (PVA) hydrogel, was tested with human bone marrow-derived mesenchymal stem cells (hBMSCs) on a bilateral cavernous nerve injury (BCNI) rat model. In vitro analysis showed that the hFDM/PVA + hBMSCs patches significantly increased neural development markers. In vivo experiments demonstrated that the rats treated with the hFDM/PVA patch had higher ICP/MAP ratios, higher ratios of smooth muscle to collagen, increased nNOS content, higher levels of eNOS protein expression, and higher cGMP levels compared to the BCNI group. These results indicate that the hFDM/PVA patch is effective in promoting angiogenesis, smooth muscle regeneration, and nitrergic nerve regeneration, which could contribute to improved erectile function in post-prostatectomy ED. Full article

The hexanic extract of Serenoa repens (HESr) has been in use for decades as an effective, safe and well-tolerated therapy for relieving bothersome lower urinary tract symptoms (LUTS) associated with benign prostate hyperplasia (BPH). This manuscript gives an overview of HESr as monotherapy for LUTS/BPH treatment and focuses on the currently available literature investigating the possible clinical benefits of HESr combination therapy with α-blockers. Combination therapy of HESr with α-blockers has been gaining significant interest in recent years, as an increasing body of evidence shows the beneficial pharmacological effects that HESr treatment can add to standard first-line treatment with α-blockers. By reducing persistent Prostatic Inflammatory Status (PIS), commonly present in LUTS/BPH patients, HESr complements the relaxation of prostate smooth muscle induced by α-blockers, thus providing additional symptom relief. Data suggest that patients harbouring PIS and having a specific clinical profile might especially benefit from the combination therapy. Future therapeutic efforts may take advantage of more personalised strategies for LUTS/BPH management. Full article

Isoflavone-rich legumes, including soy, are used for food production, as dietary supplements and in traditional medicine. Soy consumption correlates negatively with benign prostatic hyperplasia (BPH) and voiding symptoms. However, isoflavone effects on the prostate are hardly known. Here, we examined the effects on human prostate smooth muscle contractions and stromal cell growth, which are driving factors of voiding symptoms in BPH. Smooth muscle contractions were induced in prostate tissues from radical prostatectomy. Growth-related functions were studied in cultured stromal cells (WPMY-1). Neurogenic, α₁-adrenergic and non-adrenergic contractions were strongly inhibited with 50 µM and by around 50% with 10 µM genistein. Daidzein inhibited neurogenic contractions using 10 and 100 µM. Agonist-induced contractions were inhibited by 100 µM but not 10 µM daidzein. A combination of 6 µM genistein with 5 µM daidzein still inhibited neurogenic and agonist-induced contractions. Proliferation of WPMY-1 cells was inhibited by genistein (>50%) and daidzein (<50%). Genistein induced apoptosis and cell death (by seven-fold relative to controls), while daidzein induced cell death (6.4-fold) without apoptosis. Viability was reduced by genistein (maximum: 87%) and daidzein (62%). In conclusion, soy isoflavones exert sustained effects on prostate smooth muscle contractions and stromal cell growth, which may explain the inverse relationships between soy-rich nutrition, BPH and voiding symptoms. Full article

Prostate cancer (PC) bone metastases can be divided into transcriptomic subtypes, by us termed MetA-C. The MetB subtype, constituting about 20% of the cases, is characterized by high cell cycle activity, low androgen receptor (AR) activity, and a limited response to standard androgen deprivation therapy (ADT). Complementary treatments should preferably be introduced early on if the risk of developing metastases of the MetB subtype is predicted to behigh. In this study, we therefore examined if the bone metastatic subtype and patient outcome after ADT could be predicted by immunohistochemical analysis of epithelial and stromal cell markers in primary tumor biopsies obtained at diagnosis (n = 98). In this advanced patient group, primary tumor International Society of Urological Pathology (ISUP) grade was not associated with outcome or metastasis subtype. In contrast, high tumor cell Ki67 labeling (proliferation) in combination with low tumor cell immunoreactivity for PSA, and a low fraction of AR positive stroma cells in the primary tumors were prognostic for poor survival after ADT. Accordingly, the same tissue markers were associated with developing metastases enriched for the aggressive MetB subtype. The development of the contrasting MetA subtype, showing the best response to ADT, could be predicted by the opposite staining pattern. We conclude that outcome after ADT and metastasis subtype can, at least to some extent, be predicted by analysis of primary tumor characteristics, such as tumor cell proliferation and PSA expression, and AR expression in stromal cells. Full article

Benign prostatic hyperplasia (BPH) is a disease that commonly affects elderly men. Cordycepin is an adenosine analog with a wide range of pharmacological activities including antiproliferative and prostatic smooth muscle relaxant effects. This study was designed to assess the actions of cordycepin in testosterone-induced BPH in rats. Animals were divided into six treatment groups: control, cordycepin-alone (10 mg/kg), testosterone-alone (3 mg/kg), cordycepin (5 mg/kg) + testosterone, cordycepin (10 mg/kg) + testosterone, and finasteride (0.5 mg/kg) + testosterone. Treatments were continued daily, 5 days a week, for 4 weeks. Cordycepin significantly prevented the increase in prostate weight and prostate index induced by testosterone. This was confirmed by histopathological examinations. Cordycepin antiproliferative activity was further defined by its ability to inhibit cyclin-D1 and proliferating cell nuclear antigen (PCNA) expression. In addition, cordycepin exhibited significant antioxidant properties as proven by the prevention of lipid peroxidation, reduced glutathione diminution, and superoxide dismutase exhaustion. This was paralleled by anti-inflammatory activity as shown by the inhibition of interleukin-6, tumor necrosis factor-α, and nuclear factor-κB expression in prostatic tissues. It also enhanced apoptosis as demonstrated by its ability to enhance and inhibit mRNA expression of Bax and Bcl2, respectively. Western blot analysis indicated that cordycepin augmented phospho-AMP-activated protein kinase (p-AMPK) and inhibited p-AKT expression. Collectively, cordycepin has the ability to prevent testosterone-induced BPH in rats. This is mediated, at least partially, by its antiproliferative, antioxidant, anti-inflammatory, and pro-apoptotic actions in addition to its modulation of AMPK and AKT activation. Full article

Botulinum toxin A (Botox) had been considered a promising drug that has an effect on functional disorders of the lower urinary tract. Because Botox exhibits anti-inflammatory and antispasmodic effects, Botox injection into the bladder can decrease detrusor contractility, reduce bladder hypersensitivity, and eliminate painful sensations. Injecting Botox into the bladder outlet can relax the hyperactivity of the bladder neck, and of the urethral smooth and striated muscles. Based on these therapeutic effects, Botox has been widely applied to treat lower-urinary-tract dysfunctions (LUTDs) such as overactive bladder and neurogenic detrusor overactivity. However, this treatment has not been licensed for use in other LUTDs such as interstitial cystitis, voiding dysfunction due to benign prostatic hyperplasia in men, and dysfunctional voiding in women. Botox has also not been approved for the treatment of children with overactive bladder and dysfunctional voiding; in patients with spinal cord injuries with detrusor sphincter dyssynergia and autonomic dysreflexia; or for poorly relaxed external sphincter in non-neurogenic patients. This article reviews the current knowledge regarding Botox treatment for LUTDs and discusses the potential clinical applications of Botox, as well as work that can be conducted in the future. Full article

Inhibitors of phosphodiesterase type 5 (PDE5i) are the first-line treatment for erectile dysfunction and are also used to treat pulmonary hypertension. PDE5i impedes the breakdown of nitric oxide (NO)-driven cyclic guanosine monophosphate (cGMP) in smooth muscle cells of the vascular bed, acting as a potent vasodilator. In heart failure, cGMP signaling is altered. The modulation of cGMP has therefore emerged as a potential therapeutic option for heart failure. In this prospective observational study, we aim to investigate whether tadalafil, a long-acting PDE5i used for erectile dysfunction, could also improve diastolic function assessed by cardiac ultrasound. A total of 23 patients were enrolled, undergoing nerve-sparing robot-assisted radical prostatectomy for prostate cancer and treated with 20 mg tadalafil on alternate days to recover erectile function. All patients underwent tadalafil treatment for at least 6 months. Participants underwent a clinical and cardiac ultrasound with color Doppler assessment at baseline, after 3 months, and after 6 months. At 6 months, no significant difference was found apart from lower E/e’ ratio (7.4 ± 2.7 vs. 6.3 ± 1.3; p < 0.03), peak velocity of TR jet (2.4 ± 0.2 vs. 2.1 ± 0.2; p < 0.001), and PAPs (27.3 ± 3.6 vs. 22.9 ± 5.7; p < 0.005). Our prospective study shows that 6 months of erectile dysfunction therapy for secondary to radical prostatectomy is associated with a favorable effect on diastolic function, improving the E/e’ ratio and peak velocity of the TR jet. Full article