Benign Prostatic Hyperplasia In Rats Research Articles

Y-27632 targeting ROCK1&2 modulates cell growth, fibrosis and epithelial-mesenchymal transition in hyperplastic prostate by inhibiting β-catenin pathway

Benign prostatic hyperplasia (BPH) is a prevalent condition affecting the male urinary system, with its molecular mechanisms of pathogenesis remaining unclear. Y-27632, a non-isoform-selective Rho kinase inhibitor, has shown therapeutic potential in various diseases but its effects on static factors and fibrosis in BPH remain unexplored. This study investigated human prostate tissues, human prostate cell lines, and BPH rat model using immunofluorescence, flow cytometry, quantitative reverse transcription polymerase chain reaction, western blotting, and cell counting kit-8. ROCK1 and ROCK2 were significantly up-regulated in BPH tissues, correlating with clinical parameters. Y-27632 targeted the inhibition of ROCK1 & ROCK2 expression and inhibited cell proliferation, fibrosis, epithelial-mesenchymal transition (EMT), while induced cell apoptosis in a dose-dependent manner. Moreover, knockdown of either ROCK isoform inhibited fibrosis and EMT, induced apoptosis, while ROCK overexpression had the opposite effects. ROCK downregulation inhibited the β-catenin signaling pathway (such as C-MYC, Snail and Survivin) and decreased β-catenin protein stability, while inhibiting TGF-β/Smad2/3 signaling. At the in vivo level, Y-27632 reversed prostatic hyperplasia and fibrosis in BPH model rats to some extent. Our study sheds light on the therapeutic potential of Y-27632 in regulating prostate cell growth, fibrosis and EMT, and demonstrates for the first time the regulatory effect of ROCK isoforms on prostate cells, providing the basis for future research of ROCK isoform-selective inhibitors.

Hosta plantaginea (Lam.) Aschers flower modulates inflammation and amino acid metabolism by inhibiting NF-κB/MAPK/JAK-STAT/PI3K-Akt and AMPK pathways to alleviate benign prostatic hyperplasia in rats

Benign prostatic hyperplasia (BPH) is the most common urogenital disease in men with no definitive treatment. Inflammation, androgen imbalance, and oxidative stress play crucial roles in the pathogenesis of BPH. The flower of Hosta plantaginea (Lam.) Ascher is a pivotal medicinal plant in China, used to treat BPH. However, its effect and mechanism against BPH have not been clear. Our aim was to decipher the pharmacodynamics and mechanisms of H. plantaginea flower against BPH. The extract yields and HPLC-based chemoprofile of ethanolic extract (HP) and total flavonoid (TF) of H. plantaginea flowers were used as reference standard to ensure their quality. The testosterone propionate-induced BPH rat model was used to assess the effects of HP and TF. Protein expression, metabolomics, and network pharmacology analyses were performed. Twenty constituents were identified in both HP and TF, with four quantitatively analyzed using the HPLC method. HP and TF demonstrated significant therapeutic effects on BPH, including reduced prostate size and prostatic index, improved pathological injury of prostate, as well as increased levels of testosterone, superoxide dismutase, glutathione, and glutathione peroxidase, along with decreased levels of dihydrotestosterone, 5 alpha-reductase, epidermal growth factor, TNF-α, IL-1β, IL-6, and malondialdehyde. Western blotting assay indicated that HP and TF prominently inhibited the protein expression of phosphorylated p65, IκBα, JNK, p38, Erk1/2, JAK1, STAT3, PI3K, Akt, and AMPKα1 in a dose-dependent manner. Integrating metabolomics and network pharmacology analyses revealed that HP and TF observably regulated 30 differential metabolites and 11 hub genes across the aforementioned pathways, which are closely associated with amino acid metabolism. The proposed comprehensive strategy of in vivo experiments, metabolomics, and network pharmacology studies has demonstrated that HP and TF could alleviate BPH injury in rats by suppressing inflammation, androgen imbalance, oxidative stress, and amino acid metabolism through the inhibition of NF-κB, MAPK, JAK-STAT, PI3K-Akt, and AMPK pathways, which provides novel insights into the potential of H. plantaginea flower as a treatment for BPH.

Proliferative mechanism of benign prostatic hyperplasia by NLRP3 inflammasome through the complement pathway.

The expressions of complement component C5a and NLRP3 inflammasome and the antiproliferative effect of resveratrol in benign prostatic hyperplasia (BPH) model rat were analyzed to clarify the BPH proliferative mechanism. This study used the pathological stromal-dominant BPH model rat by urogenital sinus implantation (UGS). Expression of C5a, NLRP3, Caspase-1, IL-1β, and IL-18 using rat BPH tissues at 2, 3, and 8 weeks (n = 6, respectively) after UGS implantation were analyzed by qRT-PCR, western blotting analysis, and immunohistochemical (IHC) analysis. Serum IL-1β levels in BPH model and sham rats were measured by enzyme-linked immunosorbent assay. Furthermore, resveratrol, as the NLRP3 pathway inhibitor, was administered to BPH model rat to assess the antiproliferative effect on the BPH proliferative process. The proliferative effect on prostate was evaluated by Ki-67 protein expression. The expression levels of C5a, NLRP3, Caspase-1, IL-1β, and IL-18 in qRT-PCR, western blotting, and IHC were significantly upregulated in BPH tissues compared to control prostate tissues and showed increases with time (all p < 0.05). Serum IL-1β levels in BPH model rats had significantly increased compared to sham rats. On IHC, deposition of C5a, NLRP3, Caspase-1, IL-1β, and IL-18 was abundant in stromal areas of BPH. The administration of resveratrol significantly decreased prostate weight and expressions of NLRP3, IL-1β, IL-18, and Ki-67 (all p < 0.05). NLRP3 inflammasome activation by complement C5a produces IL-1β and IL-18 through Caspase-1 during the BPH proliferative process. NLRP3 inflammasome have the possibilities to be a therapeutic target for BPH proliferation by inhibiting the NLRP3 inflammasome pathway.

Asiatic acid mitigates testosterone-induced benign prostatic hyperplasia in rats via activation of PPAR-γ.

Prostate enlargement due to benign prostate hyperplasia (BPH) is a common, progressive disorder in elderly males with increasing prevalence. It causes devastating lower urinary tract symptoms with no satisfactory medication. Asiatic acid (AA), a natural pentacyclic triterpenoid, is known to have antiproliferative, antioxidant, and anti-inflammatory activities. The aim of this study was to evaluate the possible preventive activities of AA against BPH induced by testosterone in rats. Finasteride (0.5 mg/kg) was used as a reference drug. AA (10 or 20 mg/kg) administration inhibited the rise in prostatic weight and index induced by testosterone. Histopathological staining proved that AA mitigated the pathological features of BPH induced by testosterone, which was reflected as lower glandular epithelial in AA-treated groups. Also, the administration of AA along with testosterone restored the redox valance by inhibiting lipid peroxidation, and MDA production, and restoring the activities of superoxide dismutase (SOD) and catalase (CAT) activities. Also, AA reduced prostate interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and nuclear factor-kappa B (NF-κB) protein expression. In addition, AA modulated mRNA expression of Bax and Bcl-2 in favor of apoptosis. The effects of AA (20 mg/kg) were comparable to those of finasteride. Further, AA ameliorated the rise in insulin-like growth factor 1 receptor (IGF-1R) mRNA expression. This was associated with the enhancement of the prostatic content of PPAR-γ. It can be concluded that AA mitigated the features of BPH induced by testosterone in rats. This involves antioxidant, anti-inflammatory and pro-apototic activities of AA as well as its ability to down-regulate IGF-1R expression and enhance PPAR-γ concentration in prostatic tissues.

Diterpene glycosides from Fructus Rubi ameliorates benign prostatic hyperplasia in rats through the androgen and TGF-β/Smad signaling pathway

Fructus Rubi (FR), a food material with medicinal value, is used in traditional Chinese medicine (TCM) for treatment of various kidney-related problems, such as impotence, spermatorrhea, and frequent urination. It is also frequently used to produce diverse functional foods in China. The purpose of this research was to assess the therapeutic effects of FR diterpene glycosides on RWPE-1 epithelial cell (RWPE-1), a human normal prostatic epithelial cell, and benign prostate hyperplasia (BPH) rats, both of which had been exposed to dihydrotestosterone (DHT) and testosterone propionate (TP), respectively, and to investigate the mechanism of action. Target proteins that could stably bind to certain diterpene glycosides were screened through drug affinity responsive target stability combined with mass spectrometry (DARTS/MS). DHT-induced RWPE-1cells were used to detect drug activity. TP was subcutaneously injected to induce BPH in rats. The extract of diterpene glycosides from FR (FDS) was orally administered for 28 days. The DHT levels in the serum and prostate tissue of the rats were measured through enzyme-linked immunosorbent assay (ELISA), and to analyze cell proliferation and epithelial-mesenchymal transition (EMT), the protein expression of prostate-specific antigen (PSA), androgen receptor (AR), steroid 5α-reductase type 2 (SRD5A2), proliferating cell nuclear antigen (PCNA), S100 calcium-binding protein A2 (S100A2), transforming growth factor-β1 (TGF-β1), E-cadherin, vimentin, and Smad4 was determined through western blotting (WB), immunohistochemistry (IHC), or immunofluorescence (IF). FDS reduced the proliferation of DHT-induced RWPE-1cells. It also significantly inhibited rat prostate enlargement; decreased DHT levels in the serum and prostate tissue; inhibited the protein expression of AR, PSA, PCNA, S100A2, TGF-β1, E-cadherin, and Smad4; and increased the protein expression of E-cadherin. The present study is the first to report that diterpene glycosides isolated from FR inhibited BPH at the cellular level, regulated the proliferation of prostate cells through the androgen signaling pathway, and prevented EMT in the prostate through the S100A2-mediated TGF-β/Smad signaling pathway. These results indicate that FDS is a promising multitarget therapy for BPH.

Ixeris polycephala Extract Alleviates Progression of Benign Prostatic Hyperplasia via Modification of Proliferation, Apoptosis, and Inflammation.

Benign prostatic hyperplasia (BPH) is a urogenital disorder that is common in aging men. Ixeris polycephala (IP) is used in traditional medicine and contains pharmacologically active compounds. However, the effect for BPH progression has not been elucidated. We herein examined the protective potential of IP extract on a testosterone-induced model of BPH in rats. To generate the BPH model, daily subcutaneous administration of testosterone was applied for 4 weeks. During this period, the rats were also administered a daily oral gavage of IP (150 mg/kg), finasteride (positive control), or vehicle. Testosterone treatment was associated with a significantly higher prostate-to-body weight ratio, serum dihydrotestosterone (DHT) level, and prostatic gene expression of 5α-reductase compared to untreated controls. Notably, IP plus testosterone co-treatment was associated with decreased epithelial thickness, down-regulation of proliferating cell nuclear antigen (PCNA) and cyclin D1, and upregulation of pro-apoptotic signaling molecules. IP co-treatment also down-regulated pro-inflammatory cytokines, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) and decreased inflammatory cell infiltration compared to the levels seen in the testosterone-induced BPH. IP appears to protect rats against the progression of testosterone-induced BPH by alleviating prostate cell growth and inflammatory responses, and thus may have potential for clinical use against BPH progression.

Combining untargeted and targeted metabolomics to reveal the mechanisms of herb pair Anemarrhena asphodeloides Bunge and Phellodendron chinense C. K. Schneid on benign prostatic hyperplasia

Ethnopharmacological relevanceAnemarrhena asphodeloides Bunge (Ane) and Phellodendron chinense C. K. Schneid (Phe) is classical herb pair in traditional Chinese medicine, commonly used to ameliorate the symptoms of Benign Prostatic Hyperplasia (BPH). However, the mechanisms underlying this effect are remained indistinct. Aim of the studyThis study aimed to clarify potential therapeutic mechanisms of herb pair on BPH from a metabolic perspective. Materials and methodsTestosterone propionate-induced BPH rat model was established, prostatic parameters, histopathology and the levels of serum dihydrotestosterone (DHT) and testosterone (T) were used to evaluate the pharmacological effect of the herb pair on BPH. Subsequently, untargeted metabolomics of prostate tissues samples was performed by UHPLC-Q-Exactive-Orbitrap-MS, followed by multivariate statistical analysis. Targeted metabolomics by UHPLC-QQQ-MS was further utilized to verify and supplement the results of lipids and amino acids found by untargeted metabolomics, clarifying the relationship between disease, herbal pair and metabolism pathway. ResultsThe study found that Ane-Phe could relieve the progression of BPH and regulate metabolic imbalances. The levels of 13 metabolites decreased and 11 increased in prostatic tissues including glycerolphospholipid, arachidonic acid, citric acid and so on, these altered metabolites were primarily associated with TCA cycle, arachidonic acid metabolism, lipid metabolism and amino acid metabolism. Furthermore, targeted metabolomics was fulfilled to further analyze the lipid metabolism disorders, the levels of 5 lipids in serum and 21 in prostatic tissues were changed in the herb pair group compared to the model group, which closely related to glycerophospholipid, sphingolipid and glycerolipid metabolism. Besides, amino acid metabolism may be regulated by activating arginine metabolism pathway. ConclusionsIn this study, the combination of untargeted metabolomics and targeted metabolomics was applied to explore therapeutic mechanisms of Ane-Phe on BPH. In summary, Ane-Phe could improve the levels of endogenous metabolites by regulating multiple metabolic pathways and plays a role in energy supply, anti-inflammation and oxidative stress in BPH treatment.

Anti-proliferative effect and mechanisms of Peony pollen on BPH via inhibition of inflammatory factors, oxidative damage and modulation of gut microbiota and SCFAs metabolism

BackgroundPeony pollen (PP) has long been used as a functional food and herbal medicine. However, the potential protective effect and mechanisms of PP on benign prostatic hyperplasia (BPH) are still unclear. This study aims to explore the therapeutic effect and potential mechanisms of PP on BPH. MethodsThe rat model of BPH was induced by subcutaneous injection of testosterone propionate (TP). Meanwhile, the model rats were treated with PP, and physiological and biochemical indexes, the steroid 5 alpha reductase 2 (SRD5A2), proliferating cell nuclear antigen (PCNA) and androgen receptor (AR) expressions, gut microbiota and short-chain fatty acids (SCFAs) were measured. ResultsThe results showed that the wet weight of prostate tissue and the thickness of epithelium decreased treated with PP significantly. In addition, the PP also adjusted the androgen levels, down-regulated the SRD5A2, PCNA and AR expressions, inhibited the expression of inflammatory factors including interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and reduced oxidative damage in BPH rats. It is worth noting that PP can obviously regulate the gut microbiota disorder of BPH rats, increase the abundance of beneficial bacteria (e.g., Romboutsia), reduce the abundance of pathogenic bacteria (e.g., norank_f_Oscillospiraceae), and stimulate the increase of SCFAs content. ConclusionsThese data showed that PP can resist abnormal proliferation of the prostate by down regulation of SRD5A2, PCNA and AR expressions, attenuating oxidation stress and inflammatory damages and directly regulate the gut microbiota, especially the Firmicutes, and increased the level of SCFAs to ameliorate BPH. Therefore, PP might be an excellent natural plant for the development of BPH-related drugs or dietary supplements.

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.

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&lt; 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&lt; 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&lt; 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.

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.

Syzygium malaccense leaves methanol extract modulate some biochemical and inflammatory markers and prostate histology of testosterone-estradiol valerate induced benign prostatic hyperplasia in rats.

The effect of Syzygium malaccense methanol leaf extract (SMLE) on some parameters of testosterone-estradiol valerate induced benign prostatic hyperplasia (BPH) in rats was assayed. Thirty male albino rats were used and they were grouped as: Control: received 1 mL/kg olive oil (oral and subcutaneous); BPH: received subcutaneously 9 mg/kg dihydrotestosterone (DHT)+0.9 mg/kg estradiol valerate (ESV) and orally 1 ml/kg olive oil; finasteride: received 9 mg/kg of DHT+0.9 mg/kg ESV (subcutaneously) and 5 mg/kg finasteride (orally) and test groups 1 and 2: received 9 mg/kg of DHT+0.9 mg/kg ESV (subcutaneously) and 200 and 400 mg/kg SMLE (orally). The duration of the treatment was 28 days. The BPH group had increased prostatic total proteins, oxidative stress, interleukin 8, tumor necrosis factor-α, prostate weights, serum concentrations of prostate specific antigen, estradiol, follicle stimulating hormone, and C-reactive protein, dyslipidaemia, altered prostate histology and hormonal levels but had no significant change (p>0.05) in haematological indices relative to the control. Finasteride or S. malaccense modulated most of these parameters as corroborated by prostate histology. Acute toxicity study indicated the non-toxicity of SMLE. SMLE showed strong in vitro antioxidant activity which corroborated its in vivo antioxidant activity. The study showed that S. malaccense could be useful in the management of BPH.

The Combination of Curcumae Radix and Syzygium Aromaticum Extracts Mitigates Benign Prostatic Hyperplasia through Anti-Proliferative and Anti-Inflammatory Effects.

Benign prostatic hyperplasia (BPH) is a urinary tract disorder that primarily affects geriatric males. Natural materials have been developed to treat and prevent symptoms of BPH. However, a few natural functional foods has been conclusively proven to cure or prevent symptoms of BPH. The study aimed to investigate the anti-proliferative mechanism of Curcumae Radix (CR) and Syzygium aromaticum (SA) extracts using RWPE-1 cells and testosterone propionate (TP)-induced BPH rats. In vitro experiments were performed to assess the synergistic anti-proliferative effects of an equal mixture of CR and SA extracts on TP-treated RWPE-1 cells. In animal experiments, TP-induced BPH rats were administrated with saline, CR and SA extracts at 50, 100, and 200 mg/kg or finasteride at 1 mg/kg daily for 6 weeks. Body weight, prostate weight, dihydrotestosterone (DHT), androgen receptor (AR), and prostate-specific antigen (PSA) levels were measured. Additionally, extracellular signal-regulated kinase and NF-κB levels, oxidative stress, and inflammatory stress responses in the prostate were also analyzed. In this study, the combination of CR and SA extracts synergistically inhibited cell proliferation compared with the effect of each extract in TP-treated RWPE-1 cells. CR and SA extracts inhibited increasing of prostate weight, thickness of prostate epithelium, the level of PSA and DHT in serum. The expression of protein and gene of PSA and AR in prostate of TP-induced BPH rats were also suppressed by the administration of CR and SA extracts. Furthermore, reactive oxygen species and inflammation axis, NOX4-iNOS-COX2 and its associated representative inflammatory cytokine, interleukin-8 were also reduced in the CR and SA extracts-administered BPH rats. The results suggest that the combination of CR and SA extracts improves BPH through its anti-inflammatory and anti-oxidative effects, demonstrating great potential as an anti-BPH medicine.

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.