Benign Prostatic Hyperplasia In Rats Research Articles

Evaluation and Comparison of the Preventive Role of Nebivolol and Alpha- Tocopherol in Testosterone-Induced Benign Prostatic Hyperplasia in Rats

Objective: To evaluate and compare the preventive role of Nebivolol and Alpha Tocopherol on testosterone-induced benign prostatic hyperplasia in rats. Study Design: Laboratory-based experimental study Place and Duration of Study: Department of Pharmacology and Pathology, Army Medical College, Rawalpindi, in collaboration with National Institute of Health (NIH), Islamabad Pakistan, from Dec 2021 to Jun 2022. Methodology: One hundred fifty healthy male Sprague-Dawley rats were procured from the NIH, Islamabad. They were placed into five groups, each with 30 rats. Results: Out of a total 150 sample of five groups, the mean prostatic index in Group-A, Group-B, Group-C, Group-D, and Group-E were 1.49±0.09, 2.35±0.48, 1.87±0.11, 1.72±0.04 and 1.68±0.08 respectively (p-value< 0.001). Mean Prostate Specific Antigen in Group-A, Group-B, Group-C, Group-D and Group-E was 0.19±0.02, 0.23±0.01, 0.18±0.02, 0.18±0.02 and 0.16±0.02 respectively (p-value< 0.001). On gross examination, in Group-A, all (100%) prostate samples were normal-sized. In Group-B, all (100%) prostate samples were enlarged. In Group-C, 53.3% were mild, and 47.7% of samples were moderately enlarged. In Group-D, 73.3% of samples were mildly enlarged, and 26.7% were moderately enlarged. In Group E, 26.7% of samples were normal, and 73.3% were mildly enlarged (p-value< 0.001). Conclusion: Prostatic index is markedly declined following treatment with the combination of Nebivolol and Alpha-Tocopherol. There is also a declining trend in Prostate Specific Antigen following treatment with a combination of Nebivolol and Alpha-Tocopherol.

Effects of Taraxaci Herba (Dandelion) on Testosterone Propionate-Induced Benign Prostatic Hyperplasia in Rats.

Benign prostatic hyperplasia (BPH) is the non-malignant enlargement of the prostate, associated with lower urinary tract symptoms (LUTSs). Taraxaci Herba (TH), commonly known as dandelion, has traditionally been utilized in East Asia to treat symptoms related to LUTSs. Based on this traditional use, our study aimed to explore the inhibitory effects of TH on BPH progression using a testosterone propionate-induced rat model. To induce BPH, male Sprague Dawley rats were castrated and injected subcutaneously with testosterone propionate (3 mg/kg/day) for 28 days. Concurrently, TH extract was administered orally at doses of 100 and 300 mg/kg/day throughout the four-week period of testosterone propionate injections. The TH extract significantly reduced both the absolute and relative weights of the prostate, along with histopathological changes in the gland. Moreover, it lowered serum levels of testosterone and dihydrotestosterone and reduced the expression of the androgen receptor in the prostate. Additionally, the TH extract modulated the protein expressions of Bax and Bcl-2, which are key regulators of apoptosis in prostate cells. Collectively, our findings suggest that TH inhibits BPH development partially by modulating androgen signaling and inducing apoptosis within the prostate.

Therapeutic effect of aqueous extract from Ampelocissus africana (Lour) Merr rhizomes on testosterone-induced benign prostatic hyperplasia in Wistar rats

Introduction: Ampelocissus africana is a medicinal plant used to treat several diseases, including those affecting the prostate. This study investigated the effects of the aqueous extract of rhizomes from Ampelocissus africana (AAA) on a testosterone propionate (TP)-induced benign prostatic hyperplasia (BPH) model. Methods: The effect of the extract at 50, 150, and 300 mg/kg on BPH in male rats was assessed using daily subcutaneous injections of 3 mg/kg TP for four consecutive weeks. After the induction schedule, physical parameters, prostate index (PI), serum biochemical parameters, homogenate antioxidant, enzyme parameters, and prostates histopathological studies were carried out. Triterpenes and sterols were also assessed. Results: Treatment with AAA reduced the PI level in a dose-dependent manner (up to 75.91% at the dose of 300 mg/kg). The inflammatory marker measured in the present study, namely C-reactive protein, increased significantly in the BPH group and improved with the treatments. In addition, AAA reduced oxidative stress by decreasing the malondialdehyde (MDA) level and increasing the catalase (CAT) and superoxide dismutase (SOD) levels in comparison to the positive control group. A histopathological examination corroborated the result of the analysis of the physical and biochemical parameters. The study also showed interesting levels of triterpenes (119.5 ± 4.5 mg UAE/g) and sterols (104.6 ± 3.06 mg CE/g). Conclusion: These results suggest that the aqueous extract of Ampelocissus africana could be used as a natural herbal therapy to treat BPH.

MiR-1202 regulates BPH-1 cell proliferation, apoptosis, and epithelial-to-mesenchymal transition through targeting HMGCL.

Benign prostatic hyperplasia (BPH) is the expansion of the prostate gland that results in urinary symptoms. Both the epithelial-to-mesenchymal transition (EMT) and the Wnt signaling pathway are associated with BPH pathology. In this study, we find that miR-1202 is increased in BPH samples. Overexpression of miR-1202 in TGF-β-treated BPH-1 cells enhances cell survival and DNA synthesis and inhibits cell apoptosis, whereas miR-1202 inhibition partially abolishes the effects of TGF-β on BPH-1 cells. miR-1202 overexpression reduces E-cadherin level but elevates vimentin, N-cadherin, and snail levels, whereas miR-1202 inhibition partially attenuates the effects of TGF-β on EMT markers. Regarding the Wnt/β-catenin pathway, miR-1202 overexpression significantly enhances, whereas miR-1202 inhibition partially decreases, the promotive effects of TGF-β on Wnt1, c-Myc, and cyclin D1 proteins. 3-Hydroxy-3-methylglutaryl-CoA lyase (HMGCL) is a direct downstream target of miR-1202, and miR-1202 inhibits HMGCL expression through binding to its 3'UTR. Overexpression of HMGCL significantly reduces the effect of miR-1202 overexpression on the phenotypes of BPH-1 cells by inhibiting cell survival and promoting apoptosis. Similarly, HMGCL overexpression has the opposite effects on EMT markers and the Wnt/β-catenin signaling, and markedly alleviates the effects of miR-1202 overexpression. Finally, in the BPH rat model, Ki67 and vimentin levels are elevated, but E-cadherin and HMGCL levels are reduced. In conclusion, miR-1202 is upregulated in benign prostatic hyperplasia; miR-1202 enhances epithelial cell proliferation, suppresses cell apoptosis, and promotes EMT by targeting HMGCL. The Wnt/β-catenin pathway may participate in the miR-1202/HMGCL axis-mediated regulation of BPH-1 cell phenotypes.

Abstract 6276: In vitro neuroendocrine differentiation of BPH-1 cells under beta-adrenergic stimulation

Abstract Recent studies have shown that adrenergic fibers from the sympathetic nervous system (SNS), acting through stromal β2-adrenergic receptors, play an important role in the initial phases of cancer development by promoting tumor cell survival. Recent epidemiological data suggest that β-blocker intake is associated with improved survival of prostate cancer patients. Hypertension and high blood pressure have been suggested to increase prostate cancer development suggesting that the use of β-blockers in these patients could also reduce prostate cancer risk. β-adrenoceptors signal through the cAMP/PKA pathway that is known to promote neuroendocrine differentiation (NED) in LNCaP prostate cancer cell line. While neuroendocrine (NE) cells expressing synaptophysin (SYN) represent a minor cell population in the epithelial compartment of normal prostate glands, the population of NE-like cells, exhibiting NE phenotypes and expressing NE markers, is increased in, and correlates with, cancer progression, androgen-independent state and poor prognosis. Expression of the routine tissue biomarker of prostate cancer AMACR in NE-like cells discriminates them from NE cells. Our aim was to investigate whether NED could also be associated with benign prostatic hyperplasia (BPH) as recent studies showed that an increase in neuroendocrine cell density occurred before development of BPH in hypertensive rats. Our results showed that a 10-day treatment with 100µM IBMX (blocking cAMP degradation) and 10µM forskolin (FSK, adenylate cyclase activator) to trigger sustained activation of the cAMP/PKA pathway led to an increase in SYN and AMACR expression in BPH-1 cells (qPCR and WB). Similar results were observed by combining the effect of the β-adrenoceptor agonist isoproterenol (1µM) and FSK. The same treatments reduced BPH-1 cell proliferation rates by 40% and 60%, respectively, as expected for NED. Effects on AMACR and SYN expression and cell proliferation were fully reversed by the β-blocker carvedilol (5µM). This data suggests that β-adrenoceptors could be linked to the development of NE-like cells in BPH, a non-lethal disease affecting the transition zone (TZ). As 20% of the prostate cancer occur in this TZ, this observation may need further investigation. Citation Format: Natascha Pigat, Laura N. Garrido, Coline Lefevre, Manon Baures, Vincent Goffin, Anne-Sophie Armand, Thierry Capiod. In vitro neuroendocrine differentiation of BPH-1 cells under beta-adrenergic stimulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6276.

Effects of a proprietary mixture of extracts from Sabal serrulata fruits and Urtica dioica roots (WS®1541) on prostate hyperplasia and inflammation in rats and human cells.

Introduction: Phytotherapeutics, particularly extracts from Sabal serrulata (saw palmetto) fruit or Urtica dioica (stinging nettle) root, are popular for the treatment of male lower urinary symptoms in many countries, but their mechanism of action is poorly understood. We performed in vivo and in vitro studies to obtain deeper insight into the mechanism of action of WS®1541, a proprietary combination of a Sabal serrulata fruit and an Urtica dioica root extract (WS® 1473 and WS®1031, respectively) and its components. Methods: We used the sulpiride model of benign prostatic hyperplasia in rats and tested three doses of WS®1541 in comparison to finasteride, evaluating weight of prostate and its individual lobes as well as aspects of inflammation, oxidative stress, growth and hyperplasia. In human BPH-1 cells, we studied the effect of WS®1473, WS®1031, WS®1541 and finasteride on apoptosis, cell cycle progression and migrative capacity of the cells. Results: WS®1541 did not reduce prostate size in sulpiride treated rats but attenuated the sulpiride-induced changes in expression of most analyzed genes and of oxidized proteins and abrogated the epithelial thickening. In vitro, WS®1473 and WS®1031 showed distinct profiles of favorable effects in BPH-1 cells including anti-oxidative, anti-proliferative and pro-apoptotic effects, as well as inhibiting epithelial-mesenchymal-transition. Conclusion: This data supports a beneficial effect of the clinically used WS®1541 for the treatment of lower urinary tract symptoms associated with mild to moderate benign prostate syndrome and provides a scientific rationale for the combination of its components WS®1473 and WS®1031.

Computer Prediction and Experimental Verification of Guizhi Fuling Pill in the Treatment of Benign Prostatic Hyperplasia

Objective: Benign prostatic hyperplasia (BPH) is a prevalent condition among middle-aged and elderly males. The hypoxia-inducible factor-1α (HIF-1α) / vascular endothelial growth factor A (VEGF-A) signaling pathway plays a key role in proliferative disorders. Guizhi Fuling Pill (GFP) provides significant clinical efficacy in addressing BPH and related hyperplastic ailments. This study aims to elucidate the potential involvement of the HIF-1α / VEGF-A signaling pathway in the therapeutic action of GFP against BPH. Methods: Employing network pharmacology and molecular docking techniques, the mechanism underlying GFP against BPH was anticipated. A rat model of BPH was established to validate the primary targets identified via molecular docking. Subcutaneous administration of testosterone propionate was conducted to induce the BPH rat model for experimental validation. Immunohistochemistry was performed to assess the expression of HIF-1α and VEGF-A in prostate tissue across different experimental groups. Results: The network pharmacology analysis unveiled 111 potential constituents of GFP, with key components such as ent-Epicatechin, quercetin, and Mairin exerting influence on BPH. Essential targets encompass ESR1 and HSP90AA1, with signaling pathways like HIF-1, PI3K-AKT, and VEGF prominently associated with cellular apoptosis, angiogenesis, and proliferation. Molecular docking projections underscored the propensity of core components to interact with key targets, exhibiting favorable binding characteristics. In the context of animal experiments, GFP significantly reduced the expression of HIF-1α and VEGF-A in BPH-afflicted rats as compared to the model group. Conclusion: Collectively, this investigation suggests that GFP’s therapeutic potential for BPH could be attributed to its modulation of multifaceted targets, including HIF-1α and VEGF-A.

Ethanol Extracts of Cornus alba Improve Benign Prostatic Hyperplasia by Inhibiting Prostate Cell Proliferation through Modulating 5 Alpha-Reductase/Androgen Receptor Axis-Mediated Signaling.

The aim of this study was to investigate the efficacy of ethanol extracts of Cornus alba (ECA) against benign prostatic hyperplasia (BPH) in vitro and in vivo. The prostate stromal cells (WPMY-1) and epithelial cells (RWPE-1) were used to examine the action mechanism of ECA in BPH in vitro. ECA efficacy was evaluated in vivo using a testosterone propionate (TP)-induced BPH rat model. Treatment with ECA inhibited the proliferation of prostate cells by inducing G1-phase cell cycle arrest through the regulation of positive and negative proteins. Treatment of prostate cells with ECA resulted in alterations in the mitogen-activated protein kinases and protein kinase B signaling pathways. The transcriptional binding activity of the NF-κB motif was suppressed in both ECA-treated prostate cells. In addition, treatment with ECA altered the level of BPH-associated axis markers (5α-reductase, fibroblast growth factor-2, androgen receptor, epidermal growth factor, Bcl-2, and Bax) in both cell lines. Finally, the administration of ECA attenuated the enlargement of prostatic tissues in the TP-induced BPH rat model, accompanied by histology, immunoblot, and serum dihydrotestosterone levels. These results demonstrated that ECA exerted beneficial effects on BPH both in vitro and in vivo and might provide valuable information in the development of preventive or therapeutic agents for improving BPH.

Enhancing date seed phenolic bioaccessibility in soft cheese through a dehydrated liposome delivery system and its effect on testosterone-induced benign prostatic hyperplasia in rats.

The consumption of dairy products, including soft cheese, has been associated with numerous health benefits due to their high nutritional value. However, the phenolic compounds bioaccessibility present in soft cheese is limited due to their poor solubility and stability during digestion. So, this study aimed to develop an innovative soft cheese enriched with date seed phenolic compounds (DSP) extracted ultrasonically and incorporated into homogeneous liposomes and study its attenuation effect on testosterone-induced benign prostatic hyperplasia (BPH) in rats. Date seed phenolic compounds were extracted using 98 and 50% ethanol along with water as solvents, employing ultrasonication at 10, 20, and 30-min intervals. The primary and secondary DSP-liposomes were prepared and dehydrated. The particle size, zeta potential, encapsulation efficiency, and morphology were measured. Incorporating dehydrated liposomes (1-3% w/w) into soft cheese and their impact on BPH using male Sprague-Dawley rats was assessed. After inducing BPH, rats were fed a cheese diet with dehydrated DSP-liposomes. Over 8 weeks, parameters including nutrition parameters, prostate enlargement analysis, biochemical parameters, hormones level, oxidative stress, and cytokines were analyzed. The results showed that ultrasound-assisted extraction effectively reduced the extraction time and 30 min extraction EtOH 50% was enough to extract high yield of phenolic compounds (558 mg GA/g) and flavonoids (55 mg qu/g) with high antioxidant activity (74%). The biological results indicate that prostate weight and prostate index% were diminished in the treatment groups (1 and 2) compared to the BPH control group. The high antioxidant content present in the DSP-liposomes acted as the catalyst for suppressing the responses of the inflammatory cytokines, inhibiting the anti-inflammatory IL-10 production, and suppressing the elevated levels of lipid peroxidation products compared to the BPH group. The treatment group (2) supplemented with dehydrated secondary DSP-liposomes exhibited the most significant variance (p < 0.05) as opposed to the BPH group. Liposomal encapsulation was proved to be a feasible approach for administering DSP in soft cheese, thereby establishing new functional food category possessing prophylactic properties against the advancement of BPH in rats.

Periodontitis relates to benign prostatic hyperplasia via the gut microbiota and fecal metabolome.

Periodontitis is associated with benign prostatic hyperplasia (BPH), whether it related to gut floramicrobiota and metabonomics is unclear. We established ligature-induced periodontitis (EP), testosterone-induced BPH, and composite rat models. Fecal samples were collected to detect gut microbiota by 16S rDNA sequencing and metabonomics were detected by liquid chromatography tandem mass spectrometry (LC-MS/MS). Sequencing results revealed differential gut floramicrobiota composition between EP+BPH group and other three groups. The abundances of Ruminococcus flavefaciens were significantly increased in EP+BPH group compared with other groups. Tenericutes, Mollicutes, RF39 and Ruminococcus gnavus were significantly decreased in EP+BPH group compared with BPH group, while Ruminococcus callidus and Escherichia were significantly decreased compared with EP group. For gut metabonomics, LC-MS/MS showed that fecal metabolites and seven metabolic pathways were changed in EP+BPH group, such as biosynthesis of unsaturated fatty acids, steroid hormone biosynthesis. Correlation analysis showed that the alterations of gut metabolism were significantly correlated with differential gut floramicrobiota, such as Ruminococcus callidus and Ruminococcus flavefaciens. Our study highlights the relationship of periodontitis and BPH, the alterations of gut floramicrobiota and metabolites may be involved in two diseases, which provides new idea for prevention and treatment of patients with periodontitis concurrent BPH.

YAP1 Recognizes Inflammatory and Mechanical Cues to Exacerbate Benign Prostatic Hyperplasia via Promoting Cell Survival and Fibrosis.

Chronic prostatic inflammation promotes cell survival and fibrosis, leading to benign prostatic hyperplasia (BPH) with aggravated urinary symptoms. It is investigated whether yes-associated protein 1 (YAP1), an organ size controller and mechanical transductor, is implicated in inflammation-induced BPH. The correlation between YAP1 expression and fibrosis in human and rat BPH specimens is analyzed. Furthermore, the effects of YAP1 activation on prostatic cell survival and fibrosis, as well as the underlying mechanism, are also studied. As a result, total and nuclear YAP1 expression, along with downstream genes are significantly upregulated in inflammation-associated human and rat specimens. There is a significant positive correlation between YAP1 expression and the severity of fibrosis or clinical performance. YAP1 silencing suppresses cell survival by decreasing cell proliferation and increasing apoptosis, and alleviates fibrosis by reversing epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) deposition in prostatic BPH-1 and WPMY-1 cells. Mechanistically, inflammatory stimulus and rigid matrix stiffness synergistically activate the RhoA/ROCK1 pathway to provoke cytoskeleton remodeling, thereby promoting YAP1 activation to exacerbate BPH development. Overall, inflammation-triggered mechanical stiffness reinforcement activates the RhoA/ROCK1/F-actin/YAP1 axis, thereby promoting prostatic cell survival and fibrosis to accelerate BPH progression.

Scientific Evaluation of A Unani Pharmacopoeia-Based Formulation on BPH in Animal Model

BPH (Benign prostatic hyperplasia) is a common problem of the prostate gland that affects elderly men with age and major cause of lower urinary tract symptoms (LUTS) like urgency of urination, frequency of micturition, dysuria, nocturia, dribbling, and burning of urine. If left untreated, the condition can lead to severe urinary retention, recurrent UTI, and, in severe cases, renal failure, etc. Alpha-blockers and 5-alpha reductase inhibitors (5-ARIs) are two main classes of drugs that are used in conventional therapy to treat BPH. These phytochemical therapies are extremely effective, but standard control methods have unfavorable side effects too. Conversely, evidence, though limited, has shown that alternative medicines are safer and have the potential to improve LUTS and quality of life, in addition to improving sexual dysfunction in patients with BPH. The purpose of the study is to assess the efficacy of 50% hydroalcoholic UPBF extract on BPH in TP-induced rats, and the effects of the drug were compared between the treated and untreated groups. The experimental design for anti-BPH activity was carried out following the Bhavin model. 48 Wistar rats were divided into 6 groups, with 8 rats in each group. Group 1, plane control (untreated rats), group 2, negative control (treated with TP 5 mg/kg), group 3, negative control (treated with TP+ finasteride 1 mg/kg), and groups 4,5 and 6 served as tests controls (A, B, and C) treated with TP+ UPBF extract 100 mg/kg, 150 mg/kg, and 200 mg/kg as low, medium, and high doses, respectively. BPH was induced in rats by administration of testosterone propionate (TP) in arachis oil, and treatment was done orally with a standard drug (finasteride) and a test drug (UPBF) once a day for 28 consecutive days. Before and after initiating the study, each rat was weighed and documented, and after 28 days, the collection of blood samples and the prostate gland was done under light anesthesia. The parameters of the study were accessed, like prostate weight, prostate-to-body weight ratio, histopathological investigation of the prostate, percentage of inhibition, percentage of recovery, and determination of ST and STP levels. Data from the results were expressed as the mean ± standard error of the mean (SEM). Evaluation between group results was carried out with the one-way ANOVA test followed by Tukey’s test, and the significant value of p was &lt;0.05. Both histopathological and biochemical parameter results showed significant improvements in rats treated with finasteride and UPBF extract at a dose of 200 mg/kg (p&lt;0.001). In addition, ST and STP levels showed a significant reduction in comparison with the BPH group. It can be concluded from the findings of the results in both biochemicals and histopathological parameters that the test drug (UPBF) possesses significant effects against the TP-induced BPH in rats. The findings suggested that the test drug can be used independently in the management of BPH as well as for lower urinary tract symptoms.

Fermented rape pollen powder can alleviate benign prostatic hyperplasia in rats by reducing hormone content and changing gut microbiota.

Benign prostatic hyperplasia (BPH) can cause urethral compression, bladder stone formation, and renal function damage, which may endanger the life of patients. Therefore, we aimed to develop plant-based preparations for BPH treatment with no side effects. In this study, the Lactiplantibacillus plantarum 322Hp, Lactobacillus acidophilus 322Ha, and Limosilactobacillus reuteri 322Hr were used to ferment rape pollen. The fermented rape pollen was subsequently converted into fermented rape pollen powder (FRPP) through vacuum freeze-drying technology. After fermenting and drying, the bioactive substances and antioxidant capacity of FRPP were significantly higher than those of unfermented rapeseed pollen, and FRPP had a longer storage duration, which can be stored for over one year. To investigate the therapeutic effect of FRPP on BPH, a BPH rat model was established by hypodermic injection of testosterone propionate. The BPH rats were treated differently, with the model group receiving normal saline, the positive control group receiving finasteride, and the low, medium, and high dose FRPP group receiving FRPP at doses of 0.14 g/kg/d, 0.28 g/kg/d, and 0.56 g/kg/d, respectively. The results indicate that medium dose FRPP reduced the levels of hormone such as testosterone, dihydrotestosterone, and oestradiol in rats with BPH by about 32%, thus bringing the prostate tissue of BPH rats closer to normal. More importantly, medium dose FRPP treatment had a significant effect on the composition of gut microbiota in rats with BPH, increasing the levels of beneficial genera (such as Coprococcus and Jeotgalicoccus), and decreasing the levels of harmful pathogens (such as Turicibacter and Clostridiaceae_Clostridium) in the gut. This study showed that medium dose FRPP reduced the hormone level and regulated the unbalanced gut microbiota in BPH rats, thereby alleviating BPH.

Diacerein provokes apoptosis, improves redox balance, and downregulates PCNA and TNF-α in a rat model of testosterone-induced benign prostatic hyperplasia: A new non-invasive approach.

One of the most prevalent chronic conditions affecting older men is benign prostatic hyperplasia (BPH), causing severe annoyance and embarrassment to patients. The pathogenesis of BPH has been connected to epithelial proliferation, inflammation, deranged redox balance, and apoptosis. Diacerein (DIA), the anthraquinone derivative, is a non-steroidal anti-inflammatory drug. This study intended to investigate the ameliorative effect of DIA on the prostatic histology in testosterone-induced BPH in rats. BPH was experimentally induced by daily subcutaneous injection of testosterone propionate for four weeks. The treated group received DIA daily for a further two weeks after induction of BPH. Rats' body and prostate weights, serum-free testosterone, dihydrotestosterone, and PSA were evaluated. Prostatic tissue was processed for measuring redox balance and histopathological examination. The BPH group had increased body and prostate weights, serum testosterone, dihydrotestosterone, PSA, and oxidative stress. Histologically, there were marked acinar epithelial and stromal hyperplasia, inflammatory infiltrates, and increased collagen deposition. An immunohistochemical study showed an increase in the inflammatory TNF-α and the proliferative PCNA markers. Treatment with DIA markedly decreased the prostate weight and plasma hormones, improved tissue redox balance, repaired the histological changes, and increased the proapoptotic caspase 3 expression besides the substantial reduction in TNF-α and PCNA expression. In conclusion, our study underscored DIA's potential to alleviate the prostatic hyperplastic and inflammatory changes in BPH through its antioxidant, anti-inflammatory, antiproliferative, and apoptosis-inducing effects, rendering it an effective, innovative treatment for BPH.

Mechanism of RhoA regulating benign prostatic hyperplasia: RhoA-ROCK-β-catenin signaling axis and static & dynamic dual roles

BackgroundThe pathogenesis of benign prostatic hyperplasia (BPH) has not been fully elucidated. Ras homology family member A (RhoA) plays an important role in regulating cell cytoskeleton, growth and fibrosis. The role of RhoA in BPH remains unclear.MethodsThis study aimed to clarify the expression, functional activity and mechanism of RhoA in BPH. Human prostate tissues, human prostate cell lines, BPH rat model were used. Cell models of RhoA knockdown and overexpression were generated. Immunofluorescence staining, quantitative real time PCR (qRT-PCR), Western blotting, cell counting kit-8 (CCK-8), flow cytometry, phalloidine staining, organ bath study, gel contraction assay, protein stability analysis, isolation and extraction of nuclear protein and cytoplasmic protein were performed.ResultsIn this study we found that RhoA was localized in prostate stroma and epithelial compartments and was up-regulated in both BPH patients and BPH rats. Functionally, RhoA knockdown induced cell apoptosis and inhibited cell proliferation, fibrosis, epithelial-mesenchymal transformation (EMT) and contraction. Consistently, overexpression of RhoA reversed all aforementioned processes. More importantly, we found that β-catenin and the downstream of Wnt/β-catenin signaling, including C-MYC, Survivin and Snail were up-regulated in BPH rats. Downregulation of RhoA significantly reduced the expression of these proteins. Rho kinase inhibitor Y-27632 also down-regulated β-catenin protein in a concentration-dependent manner. However, overexpression of β-catenin did not affect RhoA-ROCK levels, suggesting that β-catenin was the downstream of RhoA-ROCK regulation. Further data suggested that RhoA increased nuclear translocation of β-catenin and up-regulated β-catenin expression by inhibiting its proteasomal degradation, thereby activating Wnt/β-catenin signaling. Overexpression of β-catenin partially reversed the changes in cell growth, fibrosis and EMT except cell contraction caused by RhoA downregulation. Finally, Y-27632 partially reversed prostatic hyperplasia in vivo, further suggesting the potential of RhoA-ROCK signaling in BPH treatment.ConclusionOur novel data demonstrated that RhoA regulated both static and dynamic factors of BPH, RhoA-ROCK-β-catenin signaling axis played an important role in the development of BPH and might provide more possibilities for the formulation of subsequent clinical treatment strategies.

Bushen Tongluo formula ameliorated testosterone propionate-induced benign prostatic hyperplasia in rats

BackgroundBenign prostatic hyperplasia (BPH) is a common disease in older men worldwide. However, there is currently no effective treatment for BPH. Bushen Tongluo Formula (Kidney-supplementing and collaterals-unblocking formula [KCF]) is a traditional Chinese medicine formula commonly used to ameliorate the symptoms of BPH, although the specific molecular mechanisms remain unclear. PurposeWe aimed to discover the effects and potential mechanisms of KCF against BPH. MethodsSixty male SD rats were randomly assigned to one of six group (n = 10): control, low-dosage KCF, medium-dosage KCF, high-dosage KCF, BPH model, and finasteride. A rat model of BPH was established by surgical castration followed by subcutaneous injection of testosterone propionate (TP) for 4 weeks. After treatment, the prostate index, histopathological staining, serum levels of estradiol (E2) and dihydrotestosterone (DHT), protein/mRNA levels of E-cadherin, TGF-β1, caspase-3, Ki67, and vimentin, abundances of serum metabolites, and the proliferation, cell cycle, and apoptosis of BPH-1 cells were documented. ResultsKCF treatment for 4 weeks reduced the prostate volume and prostate index, alleviated histopathological changes to the prostate of rats with TP-induced BPH, decreased serum levels of E2 and DHT, reduced protein/mRNA levels of TGF-β1 and vimentin, and increased E-cadherin levels. Moreover, KCF-spiked serum inhibited proliferation of BPH-1 cells, blocked the cell cycle, and promoted apoptosis. KCF was also found to regulate the contents of three metabolites (D-maltose, citric acid, and fumaric acid). ConclusionThe present study was the first to report that KCF exhibited therapeutic effects against BPH by regulating energy metabolism and inhibiting epithelial–mesenchymal transition in prostate tissues. Hence, KCF presents a viable treatment option for BPH.

Canagliflozin alleviates experimentally induced benign prostate hyperplasia in a rat model: exploring potential mechanisms involving mir-128b/EGFR/EGF and JAK2/STAT3 signaling pathways through in silico and in vivo investigations

Benign prostatic hyperplasia (BPH) poses a significant health concern amongst elderly males. Canagliflozin (Cana), a selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, has a powerful anti-inflammatory influence. Nevertheless, its role in treating BPH has not been clarified. Therefore, the study aimed to investigate the potential ameliorative effect of Cana on experimentally induced BPH in rats and explore the underlying mechanisms compared to the standard finasteride (Fin). The study employed histological analysis, biochemical assays using ELISA, and western blotting. Animals were categorized into four groups: Control (2.5 ml/kg CMC, orally + 3 ml/kg olive oil, subcutaneous), BPH (3 mg/kg testosterone, subcutaneous + CMC orally), Fin-treated BPH (5 mg/kg, orally), and Cana-treated BPH (5 mg/kg, orally), for 28 days. The BPH group showed obvious BPH manifestations including an increase in prostate weight (PW), prostate index (PI), dihydrotestosterone (DHT) level, and histological aberrations compared to control. Fin and Cana therapy had a comparable impact. Cana treatment significantly reduced PW and PI, besides it improved prostatic biochemical, and histopathological features compared to BPH, consistent with in silico study findings. Cana was associated with downregulation of the androgen axis, increased miR-128b expression, with a lowered expression of epidermal growth factor (EGF) and its receptor. Phosphorylation of STAT3 and its downstream proliferative markers were significantly reduced suggesting apoptotic activity. Cana markedly rescued the BPH-induced upregulation of IL-1β, and iNOS levels. Altogether, the current study demonstrates that Cana could impede BPH progression, possibly by modulating miR-128b/EGFR/EGF and JAK2/STAT3 pathways and downregulating AR, cyclin D1, and PCNA immunoreactivity.

Mechanism of Androgen-Independent Stromal Proliferation in Benign Prostatic Hyperplasia.

Benign prostatic hyperplasia (BPH) is a chronic proliferative disease showing stromal-dominant proliferation. However, the detailed proliferation mechanism has remained unclear. Although aging and androgen have been reported as definitive risk factors for BPH, recent studies have focused on the involvement of androgen-independent factors. Androgen-independent factors include ischemia, oxidative stress, metabolic syndrome, infection, autoimmune reactions, and inflammation, with inflammation in BPH tissues playing a central role in the BPH proliferative process. Inflammation in BPH tissues by various factors finally leads to tissue remodeling and stromal proliferation through the wound healing process of the prostate. To elucidate the proliferative mechanism of BPH, a study using whole-genome gene expression analysis in a stromal-dominant BPH rat model was performed and showed that immune response-related pathways and complement classical pathways are activated. Furthermore, expression analysis using this BPH rat model showed that the autoimmune reaction triggered complement pathway activation in the proliferative process of BPH. BPH is a multifactorial disease, and understanding the role of androgen-independent factors including immune responses contributes to elucidating the pathogenesis of BPH. Androgen-independent factors may lead to new therapeutic targets for BPH, and further development of this research is expected.

Combination of Lycopene and Curcumin Synergistically Alleviates Testosterone-Propionate-Induced Benign Prostatic Hyperplasia in Sprague Dawley Rats via Modulating Inflammation and Proliferation.

Benign prostatic hyperplasia (BPH) is a progressive urological disease occurring in middle-aged and elderly men, which can be characterized by the non-malignant overgrowth of stromal and epithelial cells in the transition zone of the prostate. Previous studies have demonstrated that lycopene can inhibit proliferation, while curcumin can strongly inhibit inflammation. This study aims to determine the inhibitory effect of the combination of lycopene and curcumin on BPH. To induce BPH models in vitro and in vivo, the BPH-1 cell line and Sprague Dawley (SD) rats were used, respectively. Rats were divided into six groups and treated daily with a vehicle, lycopene (12.5 mg/kg), curcumin (2.4 mg/kg), a combination of lycopene and curcumin (12.5 mg/kg + 2.4 mg/kg) or finasteride (5 mg/kg). Histologic sections were examined via hematoxylin and eosin (H&E) staining and immunohistochemistry. Hormone and inflammatory indicators were detected via ELISA. Network pharmacology analysis was used to fully predict the therapeutic mechanism of the combination of lycopene and curcumin on BPH. Combination treatment significantly attenuated prostate hyperplasia, alleviated BPH pathological features and decreased the expression of Ki-67 in rats. The upregulation of the expression of testosterone, dihydrotestosterone (DHT), 5α-reductase, estradiol (E2) and prostate-specific antigen (PSA) in BPH rats was significantly blocked by the combination treatment. The expression levels of inflammatory factors including interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α were strongly inhibited by the combination treatment. From the network pharmacology analysis, it was found that the main targets for inhibiting BPH are AKT1, TNF, EGFR, STAT3 and PTGS2, which are enriched in pathways in cancer. The lycopene and curcumin combination is a potential and more effective agent to prevent or treat BPH.

Study on mechanism of Zishen Pill treating benign prostatic hyperplasia based on serum pharmacochemistry and network pharmacology

Zishen Pill (ZSP) is a traditional Chinese medicine that is frequently used to treat Benign Prostatic Hyperplasia (BPH), however its specific mechanism of action and active ingredients are yet unknown. We used a combination of serum pharmacochemistry and network pharmacology and a series of biochemical assays to explore the action mechanism of ZSP in the treatment of BPH. The BPH rat model was created using testosterone propionate, and following oral ZSP administration, the components of ZSP in rat serum were detected by UPLC-Q-Exactive Orbitrap/MS method. A "component-target-disease" network and PPI networks were constructed on this foundation. The primary mechanism of ZSP decreasing BPH in rats was studied by KEGG pathway and GO analysis. Finally, the potential pathways and key targets were further verified in vivo by molecular biology and immunological methods. 46 substances were charactered from rat serum, and 164 anti-BPH targets were screened from the database. According to network pharmacology, the primary targets were CASP3, STAT3, JUN, and PTGS2/COX2. Three related pathways (PI3K/Akt signaling pathway, AGE-RAGE signaling pathway and EGFR tyrosine kinase inhibitor resistance) were closely related to the therapeutic effects of ZSP. The findings of molecular biology demonstrated that ZSP may bring Bcl-2, BAX, CASP3, COX2, and 5LOX protein and gene expression in BPH rats appreciably closer to that of normal rats. Additionally, ZSP can lessen the expression of inflammatory cytokines in BPH rats, including VEGF, TNF-α, CCL5, and interleukin. ConclusionThe above results suggest that ZSP may reduce BPH through inflammation/immunity and apoptosis/proliferation-related pathways. This study offers a fresh approach to investigate the basic pharmacological effects and mechanism of ZSP in the treatment of BPH.