Ixeris polycephala Extract Alleviates Progression of Benign Prostatic Hyperplasia via Modification of Proliferation, Apoptosis, and Inflammation
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SUBMITTER: Baek E
PROVIDER: S-EPMC11357589 | biostudies-literature | 2024 Aug
REPOSITORIES: biostudies-literature
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Project description:BackgroundOur previous study revealed the extract from the bark of an Amazonian tree Pao Pereira can suppress benign prostatic hyperplasia (BPH) in a rat model. Herein, we examined its inhibitory effects on human BPH cells and dissect its molecular mechanism.MethodsWe applied Pao extract to human BPH epithelial BPH-1 and prostate myofibroblast WPMY-1 cells. Cell viability, apoptosis and immunoblotting were performed, followed by gene expression profiling and gene set enrichment analysis (GSEA) to detect the differentially expressed genes and signaling pathway induced by Pao extract. Human ex vivo BPH explant organ culture was also used to examine the effects of Pao extract on human BPH tissues.ResultsPao extract treatment inhibited viability and induced apoptosis in human BPH-1 and WPMY-1 cells. Gene expression profiling and the following validation indicated that the expression levels of pro-apoptotic genes (eg. PCDC4, CHOP and FBXO32) were induced by Pao extract in both two cell lines. GSEA further revealed that Pao extract treatment was negatively associated with the activation of NFκB signaling. Pao extract suppressed the transcriptional activity of NFκB and down-regulated its target genes involved in inflammation (CXCL5, CXCL6 and CXCL12) and extracellular matrix (ECM) remodeling (HAS2, TNC and MMP13) in both cultured cells and human ex vivo BPH explants.ConclusionIn both BPH epithelial and stromal cells, Pao extract induces apoptosis by upregulating the pro-apoptotic genes and inhibiting the inflammation-associated NFκB signaling via reducing phosphorylation of NFκB subunit RelA. Our data suggest that Pao extract may be a promising phytotherapeutic agent for BPH.
| S-EPMC7231430 | biostudies-literature
Project description:Benign prostatic hyperplasia (BPH) is a widespread androgenic illness influencing elderly men. It is distinguished by prostatic epithelial and stromal muscle cell proliferation. Inflammation, oxidative stress, and apoptosis have all been interrelated to the development of BPH. Marjoram (Origanum majorana L.) is a herb with reported antiproliferative, proapoptotic, and antioxidative properties, which have not yet been studied in relation to BPH. Consequently, in this work, an ethanolic extract of O. majorana was prepared in two doses (250 and 500 mg/kg/day) to be injected into castrated rats after induction of a testosterone-BPH model. Testosterone propionate (TP) was subcutaneously injected (0.5 mg/kg/day) for one week after castration to induce BPH. Forty adult Wistar male rats were randomly allocated into five groups: control, BPH model, high and low O. majorana doses (250, 500 mg/kg/day), and finasteride (FN) (0.8 mg/kg/day) as a positive control. Treatment was continued with drugs/normal saline for 28 days. Rat's body and prostate were weighed, prostate index (PI) and % of prostate growth inhibition were calculated, serum dihydrotestosterone (DHT), prostatic content of superoxide dismutase (SOD), catalase (CAT), total antioxidant capacity (TAC), and malondialdehyde (MDA), DN damage, histopathological changes, immune expression of proliferating cell nuclear antigen (PCNA), caspase-3, α-SMA, and TGF-β1 were assessed. In addition, molecular quantitative PCR and ELISA analyses were performed to identify the expression of mRNAs and related proteins of both caspase-3 and TGF-β1 in prostate tissue from O. majorana-treated and untreated groups. Rats with BPH had significantly higher prostate weights and PI, higher DHT, DNA damage (8-hydroxyguanine, 8-OH-dG), and MDA levels with prominent PCNA, α-SMA, and TGF-β expression, but lower SOD, CAT, and TAC activity and caspase-3 expression. O. majorana (250 and 500 mg/kg/day)-treated groups revealed a decrease in prostate weights and PI, lower levels of DHT, suppressed oxidative stress, reduced tissue proliferation and fibrosis, and restored antioxidant and proapoptotic activity. Additionally, quantitative PCR and ELISA analysis showed that treatment with O. majorana significantly upregulated the expression of caspase-3 and downregulated the expression of TGF-β in prostate tissues of BPH rats. The data were confirmed by the immunohistological reactivity of these targeted markers in the prostate tissues. These effects were more significant with O. majorana 500 mg/mL/rat. In conclusion, the current study indicates the efficient use of O. majorana in the treatment of testosterone-induced BPH through its antiproliferative, proapoptotic, and antioxidative mechanisms.
| S-EPMC9219805 | biostudies-literature
Project description:BackgroundThe current drug treatments for benign prostatic hyperplasia (BPH) have negative side effects. Therefore, it is important to find effective alternative therapies with significantly fewer side effects. Our previous study revealed that Rauwolfia vomitoria (RWF) root bark extract reversed BPH development in a rat model. However, the molecular mechanism of its inhibitory effects on BPH remains largely unknown.MethodsBPH-1 and WPMY-1 cell lines derived from BPH epithelial and prostatic stromal compartments were selected to investigate how RWF extract inhibits BPH in vitro by MTT and flow cytometry assays. Microarray, quantitative real-time PCR, immunoblotting, and GFP-LC3 immunofluorescence assays were performed to evaluate the effects of RWF extract on endoplasmic reticulum stress (ER stress) and autophagic apoptosis pathways in two cell lines. A human BPH ex vivo explant assay was also employed for validation.ResultsRWF extract treatment decreased cell viability and induced apoptotic cell death in both BPH-1 and WPMY-1 cells in a concentration-dependent manner with the increase of pro-apoptotic PCDC4 protein. RWF extract induced autophagy by enhancing the levels of autophagic genes (ULK2 and SQSTM1/p62) and the LC3II:LC3I ratio, with the increase of GFP-LC3 puncta. Moreover, RWF extract activated PERK- and ATF6-associated ER stress pathways by inducing the transcriptional levels of EIF2AK3/PERK, DDIT3/CHOP and ATF6, accompanied by the reduction of BiP protein level, but not its mRNA level. Another ER stress pathway was not induced by RWF extract, as manifested by the lack of XBP1 splicing. Pharmacological inhibition of autophagy by 3-methyladenine abrogated apoptosis but not ER stress; while inhibition of ER stress by 4-phenylbutyrate alleviated the induction of autophagy and apoptosis. In addition, pretreatments with either 3-methyladenine or 4-phenylbutyrate suppressed RWF extract-induced cytotoxicity. Notably, the inductions of PERK- and ATF6-related stress pathways and autophagic apoptosis were confirmed in a human BPH ex vivo explant.ConclusionsOur data have demonstrated that RWF extract significantly suppressed the viabilities of BPH epithelial cells and BPH myofibroblasts by inducing apoptosis via upregulating ER stress and autophagy. These data indicate that RWF extract is a potential novel alternative therapeutic approach for BPH.
| S-EPMC9074266 | biostudies-literature
Project description:BackgroundBenign 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.MethodTo 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.ResultsCombination 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.ConclusionThe lycopene and curcumin combination is a potential and more effective agent to prevent or treat BPH.
| S-EPMC10343798 | biostudies-literature
Project description:BackgroundBenign prostatic hyperplasia (BPH) is a common urological condition in aging men. While dihydroartemisinin (DHA) exhibits a wide range of pharmacological activities, to date, there have been no studies examining the effects of DHA on BPH.MethodsAn in vivo BPH model was constructed in rats via daily subcutaneous injection of testosterone propionate (TP) for 28 consecutive days. Rats were randomly distributed into four groups and treated as follows: (I) control; (II) TP treatment; (III) TP and finasteride treatment (positive control); and (IV) TP and DHA treatment. At the end of the experiment, rats were sacrificed and the prostate weight, prostate index, thickness of the epithelium, collagen deposition, serum dihydrotestosterone (DHT) levels, 5α-reductase 2 (5AR-2) expression, and proliferating cell nuclear antigen (PCNA) levels in the prostate were examined. Normal human prostatic epithelial RWPE-1 cells were used in in vitro experiments to further investigate the anti-proliferative effects of DHA.ResultsTP increased the prostate weight and prostate index in rats, and this effect was reduced with DHA treatment. In addition, DHA attenuated the morphological changes and collagen deposition in the prostate tissue induced by TP. Furthermore, DHA reduced the expression of PCNA, serum DHT, and prostatic 5AR-2 in rats with TP-induced BPH. In vitro analysis revealed that DHA significantly inhibited the proliferation of TP-treated RWPE-1 cells.ConclusionsDHA significantly inhibited the development of BPH by suppressing serum DHT levels, prostatic 5AR-2 expression, and the proliferation of benign prostatic epithelial cells. Thus, DHA is a novel medicinal agent with potential therapeutic efficacy in the treatment of patients with BPH.
| S-EPMC8421977 | biostudies-literature
Project description:Benign prostatic hyperplasia (BPH) is a noncancerous urinary disorder that is common in older adult men; however, its underlying mechanisms remain unclear. Fenugreek has some biological effects, including hyperglycemia regulation, immune response modulation, and anti-cancer properties; In this study, we investigated the ameliorative effects of fenugreek seed extract (Forceterone® [FCT]) in a testosterone propionate (TP)-induced BPH animal model and its mechanisms in BPH-1 human prostate epithelial cells. Sprague Dawley (SD) rats were injected subcutaneously with TP (3 mg/kg) for 8 weeks to induce BPH while FCT was administered orally at 25, 50, and 100 mg/kg. In addition, BPH-1 cells were used to evaluate the inhibitory effects on cell proliferation and examine inflammatory cytokine expression. Treating rats with FCT decreased prostate weight, dihydrotestosterone (DHT) level, and proliferating cell nuclear antigen (PCNA) expression in the prostate. Furthermore, it decreased androgen receptor (AR), 5α-reductase 2, B-cell lymphoma 2 (Bcl-2), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and NF-κB expression in vitro and in vivo and increased Bcl-2-associated X protein (Bax) expression. FCT also inhibited cell proliferation dose dependently in BPH-1 cells. These findings showed the potential use of FCT as an alternative treatment for BPH.
| S-EPMC11818512 | biostudies-literature
Project description:BackgroundBenign prostatic hyperplasia (BPH) is characterized by increased tissue mass in the transition zone of the prostate, which leads to obstruction of urine outflow and significant morbidity in the majority of older men. Plasma markers of oxidative stress are increased in men with BPH but it is unclear whether oxidative stress and/or oxidative DNA damage are causal in the pathogenesis of BPH.MethodsLevels of 8-OH deoxyguanosine (8-OH dG), a marker of oxidative stress, were measured in prostate tissues from normal transition zone and BPH by ELISA. 8-OH dG was also detected in tissues by immunohistochemistry and staining quantitated by image analysis. Nox4 promotes the formation of reactive oxygen species. We therefore created and characterized transgenic mice with prostate specific expression of Nox4 under the control of the prostate specific ARR2PB promoter.ResultsHuman BPH tissues contained significantly higher levels of 8-OH dG than control transition zone tissues and the levels of 8-OH dG were correlated with prostate weight. Cells with 8-OH dG staining were predominantly in the epithelium and were present in a patchy distribution. The total fraction of epithelial staining with 8-OH dG was significantly increased in BPH tissues by image analysis. The ARR2PB-Nox4 mice had increased oxidative DNA damage in the prostate, increased prostate weight, increased epithelial proliferation, and histological changes including epithelial proliferation, stromal thickening, and fibrosis when compared to wild type controls.ConclusionsOxidative stress and oxidative DNA damage are important in the pathogenesis of BPH.
| S-EPMC5469601 | biostudies-literature
Project description:Despite the high prevalence of histological Benign Prostatic Hypeplasia (BPH) in elderly men, little is known regarding the molecular mechanisms and networks underlying the development and progression of the disease. Here, we explored the effects of a phytotherapeutic agent, Lipidosterolic extract of the dwarf palm plant Serenoa repens (LSESr), on the mRNA gene expression profiles of two representative models of BPH, BPH1 cell line and primary stromal cells derived from BPH. Treatment of these cells with LSESr significantly altered gene expression patterns as assessed by comparative gene expression profiling on gene chip arrays. The expression changes were manifested three hours following in vitro administration of LSESr, suggesting a rapid action for this compound. Among the genes most consistently affected by LSESr treatment, we found numerous genes that were categorized as part of proliferative, apoptotic, and inflammatory pathways. Validation studies using quantitative real-time PCR confirmed the deregulation of genes known to exhibit key roles in these biological processes including IL1B, IL1A, CXCL6, IL1R1, PTGS2, ALOX5, GAS1, PHLDA1, IL6, IL8, NFkBIZ, NFKB1, TFRC, JUN, CDKN1B, and ERBB3. Subsequent analyses also indicated that LSESr treatment can impede the stimulatory effects of certain proinflammatory cytokines such as IL6, IL17, and IL15 in these cells. These results suggest that LSESr may be useful to treat BPH that manifest inflammation characteristics. This also supports a role for inflammation in BPH presumably by mediating the balance between apoptosis and proliferation.
| S-EPMC3742245 | biostudies-literature
Project description:BackgroundBenign prostatic hyperplasia (BPH) is a common disease among older men characterized by non-malignant proliferation of epithelial cells and inflammation. Nitric oxide synthase traffic inducer (NOSTRIN) is a pleiotropic regulator of endothelial cell function and signaling and exerts anti-inflammatory, anti-proliferation, and modulating nuclear factor-kappa B (NF-κB) signaling effects. Its expression and function in BPH tissues and prostate epithelial cells are unknown. The study aims to investigate the expression and functions of NOSTRIN in BPH, and its possible molecular mechanism.MethodsThe BPH model was constructed in male Institute of Cancer Research (ICR) mice using 5 mg/kg/day testosterone propionate (TP) for 30 days, and the model was evaluated by detecting prostate index, prostate epithelial thickness, and prostate-specific antigen (PSA) expression. Dihydrotestosterone (DHT, 10 nM)-induced in vitro model of human prostate epithelial cells (RWPE-1) was established. We generated lentivirus-harboring human NOSTRIN. The mRNA expression was detected by real-time quantitative polymerase chain reaction (PCR) assay; the protein expression or localization was detected by western blot assay, immunohistochemistry, or immunofluorescence staining. Cell proliferation was assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and 5-ethynyl-2'-deoxyuridine (EdU) staining. Reactive oxygen species (ROS) production was observed by dihydroethidium staining. Nitric oxide (NO) and malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were detected using commercial kits. Enzyme-linked immunosorbent assay (ELISA) was used to determine levels of interleukin 1 beta (IL1B), interleukin 6 (IL6), interferon gamma (IFNG), and tumor necrosis factor (TNF).ResultsNOSTRIN expression was significantly inhibited in the TP-induced ICR mouse BPH model and DHT-induced model of RWPE-1 proliferation. Protein expression of the BPH-related and proliferation markers PSA and proliferating cell nuclear antigen (PCNA) was suppressed in NOSTRIN-overexpressing RWPE-1 cells exposed to DHT. NOSTRIN overexpression notably inhibited the RWPE-1 cell proliferation in vitro, as evidenced by MTT and EdU staining. NOSTRIN overexpression significantly decreased the expression of cell cycle-related proteins cyclin dependent kinase 4 (CDK4) and cyclin D1 (CCND1) in vitro. The production of ROS, NO, and lipid peroxidation products MDA was inhibited by NOSTRIN overexpression in vitro, while the SOD activity was increased. NOSTRIN overexpression reduced the mRNA expression of inflammatory mediator nitric oxide synthase 2 (NOS2) and inhibited the mRNA expression and secretion of pro-inflammatory cytokines IL1B, IL6, IFNG, and TNF in vitro. The mechanistic studies revealed an increased phosphorylation of NF-κB p65 in vivo and in vitro. Remarkably, NOSTRIN overexpression notably inhibited the protein expression of phospho-NF-κB p65 in vitro.ConclusionsNOSTRIN is involved in BPH by inhibiting proliferation, oxidative stress, and inflammation in prostate epithelial cells. These functions may act through the inhibition of NF-κB signaling.
| S-EPMC11491235 | biostudies-literature
Project description:Benign prostatic hyperplasia (BPH) is a common disease in the male population, especially in elderly men. Vanillic acid (VA), a dihydroxybenzoic derivative used as a flavoring agent, is reported to have an anti-inflammatory effect. However, there are no reports of its effects on BPH to date. BPH was induced with a pre-4-week treatment of daily subcutaneous injections of testosterone propionate (TP), and the normal control group received injections of ethanol with corn oil instead. Six weeks of further injections were done with (a) ethanol with corn oil, (b) TP only, (c) TP + finasteride, and (d) TP + VA. Finasteride was used as a positive control group. VA had protective effects on the TP-induced BPH. In the VA treatment group, the prostate weight was reduced, and the histological changes including the epithelial thickness and lumen area were restored like in the normal control group. Furthermore, in the VA treatment group, two proliferation related factors, high molecular weight cytokeratin 34βE12 and α smooth muscle actin, were significantly down-regulated compared to the TP-induced BPH group. The expressions of dihydrotestosterone and 5α-reductase, the most crucial factors in BPH development, were suppressed by VA treatment. Expressions of the androgen receptor, estrogen receptor α and steroid receptor coactivator 1 were also significantly inhibited by VA compared to the TP-induced BPH group. In addition, we established an in vitro model for BPH by treating a normal human prostatic epithelial cell line RWPE-1 with TP. VA successfully inhibited proliferation and BPH-related factors in a concentration-dependent manner in this newly established model. These results suggest a new and potential pharmaceutical therapy of VA in the treatment of BPH.
| S-EPMC5675626 | biostudies-literature