scholarly journals Piperazine-Derived α1D/1A Antagonist 1- Benzyl-N- (3-(4- (2-Methoxyphenyl) Piperazine-1-yl) Propyl) -1H- Indole-2- Carboxamide Induces Apoptosis in Benign Prostatic Hyperplasia Independently of α1-Adrenoceptor Blocking

2021 ◽  
Vol 11 ◽  
Author(s):  
Qing Xiao ◽  
Qi-Meng Liu ◽  
Ru-Chao Jiang ◽  
Kai-Feng Chen ◽  
Xiang Zhu ◽  
...  
Keyword(s):  
Benign Prostatic Hyperplasia ◽  
Cell Viability ◽  
Cell Line ◽  
Prostate Volume ◽  
Prostatic Hyperplasia ◽  
Subtype Selectivity ◽  
Prostate Growth ◽  
Apoptotic Induction

Previous studies have indicated that α1D/1A antagonist naftopidil (NAF) suppresses prostate growth by decreasing cell proliferation without affecting apoptosis and prostate volume in benign prostatic hyperplasia (BPH). A NAF-derived α1D/1A antagonist 1- benzyl-N-(3-(4-(2-methoxyphenyl) piperazine-1-yl) propyl)-1H-indole-2- carboxamide (HJZ-12) has been reported from our laboratory, which exhibits high subtype-selectivity to both α1D- and α1A- AR (47.9- and 19.1- fold, respectively) with respect to a1B-AR in vitro. However, no further study was conducted. In the present study, a pharmacological evaluation of HJZ-12 in BPH was performed on an estrogen/androgen-induced rat BPH model and human BPH-1 cell line. In vivo, HJZ-12 exhibited better performance than NAF in preventing the progression of rat prostatic hyperplasia by not only decreasing prostate weight and proliferation (similar to NAF) but also, shrinking prostate volume and inducing prostate apoptosis (different from NAF). In vitro, HJZ-12 exhibited significant cell viability inhibition and apoptotic induction in BPH-1 cell line, without presenting cell anti-proliferation properties. Intriguingly, the role of HJZ-12 on cell viability and apoptosis was an α1-independent action. Furthermore, RNA-Seq analysis was applied to screen out six anti-apoptotic genes (Bcl-3, B-lymphoma Mo-MLV insertion region 1 [Bmi-1], ITGA2, FGFR3, RRS1, and SGK1). Amongst them, Bmi-1 was involved in the apoptotic induction of HJZ-12 in BPH-1. Overall, HJZ-12 played a remarkable role in preventing the progression of prostatic hyperplasia through α1-independent apoptotic induction, indicating that it will be a multi-target effective candidate for BPH treatment.

scholarly journals Pharmacological Effects and Potential Clinical Usefulness of Polyphenols in Benign Prostatic Hyperplasia

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 450
Author(s):  
Kensuke Mitsunari ◽  
Yasuyoshi Miyata ◽  
Tomohiro Matsuo ◽  
Yuta Mukae ◽  
Asato Otsubo ◽  
...  
Keyword(s):  
Benign Prostatic Hyperplasia ◽  
Molecular Mechanisms ◽  
Prostatic Hyperplasia ◽  
Pathological Conditions ◽  
Urinary Tract Symptoms ◽  
Anti Inflammatory ◽  
Lower Urinary

Benign prostatic hyperplasia (BPH) is arguably the most common benign disease among men. This disease is often associated with lower urinary tract symptoms (LUTS) in men and significantly decreases the quality of life. Polyphenol consumption reportedly plays an important role in the prevention of many diseases, including BPH. In recent years, in addition to disease prevention, many studies have reported the efficacy and safety of polyphenol treatment against various pathological conditions in vivo and in vitro. Furthermore, numerous studies have also revealed the molecular mechanisms of the antioxidant and anti-inflammatory effects of polyphenols. We believe that an improved understanding of the detailed pharmacological roles of polyphenol-induced activities at a molecular level is important for the prevention and treatment of BPH. Polyphenols are composed of many members, and their biological roles differ. In this review, we first provide information regarding the pathological roles of oxidative stress and inflammation in BPH. Next, the antioxidant and anti-inflammatory effects of polyphenols, including those of flavonoids and non-flavonoids, are discussed. Finally, we talk about the results and limitations of previous clinical trials that have used polyphenols in BPH, with particular focus on their molecular mechanisms of action.

scholarly journals The treatment effects of flaxseed-derived secoisolariciresinol diglycoside and its metabolite enterolactone on benign prostatic hyperplasia involve the G protein-coupled estrogen receptor 1

2016 ◽  
Vol 41 (12) ◽  
pp. 1303-1310 ◽  
Author(s):  
Guan-Yu Ren ◽  
Chun-Yang Chen ◽  
Wei-Guo Chen ◽  
Ya Huang ◽  
Li-Qiang Qin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Estrogen Receptor ◽  
Benign Prostatic Hyperplasia ◽  
G Protein ◽  
Therapeutic Potential ◽  
Prostatic Hyperplasia ◽  
Docking Simulations ◽  
G Protein Coupled

Secoisolariciresinol diglucoside (SDG), a lignan extracted from flaxseed, has been shown to suppress benign prostatic hyperplasia (BPH). However, little is known about the mechanistic basis for its anti-BPH activity. The present study showed that enterolactone (ENL), the mammalian metabolite of SDG, shared the similar binding site of G1 on a new type of membranous estrogen receptor, G-protein-coupled estrogen eceptor 1 (GPER), by docking simulations method. ENL and G1 (the specific agonist of GPER) inhibited the proliferation of human prostate stromal cell line WPMY-1 as shown by MTT assay and arrested cell cycle at the G0/G1 phase, which was displayed by propidium iodide staining following flow cytometer examination. Silencing GPER by short interfering RNA attenuated the inhibitory effect of ENL on WPMY-1 cells. The therapeutic potential of SDG in the treatment of BPH was confirmed in a testosterone propionate-induced BPH rat model. SDG significantly reduced the enlargement of the rat prostate and the number of papillary projections of prostatic alveolus and thickness of the pseudostratified epithelial and stromal cells when comparing with the model group. Mechanistic studies showed that SDG and ENL increased the expression of GPER both in vitro and in vivo. Furthermore, ENL-induced cell cycle arrest may be mediated by the activation of GPER/ERK pathway and subsequent upregulation of p53 and p21 and downregulation of cyclin D1. This work, in tandem with previous studies, will enhance our knowledge regarding the mechanism(s) of dietary phytochemicals on BPH prevention and ultimately expand the scope of adopting alternative approaches in BPH treatment.

scholarly journals High-Fat Diet Induced Gut Microbiota Alterations Associating With Ghrelin/Jak2/Stat3 Up-Regulation to Promote Benign Prostatic Hyperplasia Development

2021 ◽  
Vol 9 ◽  
Author(s):  
Meng Gu ◽  
Chong Liu ◽  
TianYe Yang ◽  
Ming Zhan ◽  
Zhikang Cai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Benign Prostatic Hyperplasia ◽  
Gut Microbiota ◽  
High Fat Diet ◽  
Prostatic Hyperplasia ◽  
Prostate Tissue ◽  
High Fat ◽  
Ghrelin Receptor

The role of high-fat diet (HFD) induced gut microbiota alteration and Ghrelin as well as their correlation in benign prostatic hyperplasia (BPH) were explored in our study. The gut microbiota was analyzed by 16s rRNA sequencing. Ghrelin levels in serum, along with Ghrelin and Ghrelin receptor in prostate tissue of mice and patients with BPH were measured. The effect of Ghrelin on cell proliferation, apoptosis, and induction of BPH in mice was explored. Our results indicated that BPH mice have the highest ratio of Firmicutes and Bacteroidetes induced by HFD, as well as Ghrelin level in serum and prostate tissue was significantly increased compared with control. Elevated Ghrelin content in the serum and prostate tissue of BPH patients was also observed. Ghrelin promotes cell proliferation while inhibiting cell apoptosis of prostate cells. The effect of Ghrelin on enlargement of the prostate was found almost equivalent to that of testosterone propionate (TP) which may be attenuated by Ghrelin receptor antagonist YIL-781. Ghrelin could up-regulate Jak2/pJak2/Stat3/pStat3 expression in vitro and in vivo. Our results suggested that Gut microbiota may associate with Ghrelin which plays an important role in activation of Jak2/Stat3 in BPH development. Gut microbiota and Ghrelin might be pathogenic factors for BPH and could be used as a target for mediation.

scholarly journals Libidibia ferreaFruit Crude Extract and Fractions Show Anti-Inflammatory, Antioxidant, and Antinociceptive EffectIn Vivoand Increase Cell ViabilityIn Vitro

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Tamires Rocha Falcão ◽  
Aurigena Antunes de Araújo ◽  
Luiz Alberto Lira Soares ◽  
Iuri Brilhante de Farias ◽  
Wliana Alves Viturino da Silva ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Cell Viability ◽  
Gallic Acid ◽  
Cell Line ◽  
Crude Extract ◽  
Leukocyte Migration ◽  
Total Glutathione ◽  
Anti Inflammatory

Background.Libidibia ferrea(L. ferrea)is found throughout the northeastern region of Brazil, where it has been used in folk medicine with beneficial effects on many inflammatory disorders.Purpose. This study investigated the phytochemical composition of the crude extract and fractions ofL. ferreafruit and evaluated its anti-inflammatory and antinociceptive activitiesin vivoand effect on cell viabilityin vitro.Methods. Characterization of polyphenols present in crude extract (CE), hydroalcoholic fractions of 20-80% ethanol (CE20, CE40, CE60, and CE80), aqueous fraction (AqF), and ethyl acetate (EAF) fractions ofL. ferreafruit was performed by chromatographic analysis.Anti-inflammatory activity was evaluated by using a carrageenan-induced peritonitis model submitted to a leukocyte migration assay and myeloperoxidase activity (MPO) analysis. Total glutathione and malondialdehyde (MDA) levels were assessed to evaluate the oxidative stress level. Antinociceptive activity was evaluated by acetic acid-induced abdominal writhing and hot plate test.In vitrocell viability was determined by using MTT assay in a mouse embryonic fibroblast cell line (3T3 cells).Results. Chromatography revealed the presence of ellagic acid content in EAF (3.06), CE (2.96), and CE40 (2.89). Gallic acid was found in EAF (12.03), CE 20 (4.43), and CE (3.99).L. ferreacrude extract and all fractions significantly reduced leukocyte migration and MPO activity (p<0.001).L. ferreaantioxidant effect was observed through high levels of total glutathione and reduction of MDA levels (p<0.001). Acetic acid-induced nociception was significantly inhibited after administration ofL. ferreacrude extract and all fractions (p<0.001). Crude extract and all fractions significantly increased the viability of the 3T3 cell line (p<0.05).Conclusions. The appropriate extraction procedure preserves the chemical components ofL. ferreafruit, such as gallic acid and ellargic acid. Crude extract and fractions ofL. ferreafruit exhibited anti-inflammatory, antioxidant, antinociceptive activitiesin vivoand enhanced cell viabilityin vitro.

Rational Combinations Including a Novel Syk Inhibitor, Fostamatinib Disodium (FosD) in Diffuse Large B Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 283-283
Author(s):  
Randall M Rossi ◽  
Valerie Grose ◽  
Polly Pine ◽  
Richard I Fisher ◽  
Craig T. Jordan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Cell Viability ◽  
B Cell ◽  
Cell Line ◽  
B Cell Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
In Vivo Studies

Abstract Abstract 283 Certain malignant B-cells rely upon B-cell receptor-mediated survival signals. Spleen tyrosine kinase (Syk) initiates and amplifies the B-cell receptor-mediated signal. We and others have demonstrated that fostamatinib disodium (FosD: a prodrug of R406, a potent and specific inhibitor of Syk) induces apoptosis in lymphoma cell lines and primary tumors. A recent clinical trial has demonstrated significant clinical activity of FosD in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia, and minimal overlap in toxicities with conventional agents. Given this background, future development in B-cell NHL will include rational combinations of FosD and currently available therapies. Therefore, we conducted in vitro and in vivo studies of rational combinations including FosD, in anticipation of clinical trial development. First, using a human DLBCL cell line of GCB genotype, (OCI-Ly19), we analyzed in vitro the combination of R406 with the following agents: fludarabine, rapamycin, rituximab, bendamustine and bortezomib. Increased cytotoxicity was observed using in vitro culture assays with the addition of fludarabine, rapamycin, or rituximab to R406. Cell viability at 72 hours was 25% with R406 alone, 27% for fludarabine alone, and only 9% for the fludarabine/R406. At 48 hours, cell viability was 49% using R406 alone, 31% using rituximab alone, and 21% for rituximab/R406. At 120 hours using primary lymphoma cells (DLCL27), there were no viable cells treated with the rapamycin/FosD combination, compared with rapamycin alone (7%) or FosD alone (25%) The addition of bortezomib or bendamustine to FosD resulted in only a minimal additive increase in cytotoxicity. Results with all combinations were similar with the OCI-Ly10 human DLBCL line of ABC genotype. We then performed in vivo studies by subcutaneous transplantation of the DLBCL cell line OCI-Ly19, (engineered to express luciferase allowing for real time in vivo imaging) into immune deficient NOD/SCID mice which reproducibly formed tumors. Recipient animals were separated into uniform cohorts when the tumors were less than or equal to 500 mm3 in size. The animals were then simultaneously treated with FosD (n=7; 3 gm/kg ad. lib.; translates into 2-5 micromolar R406 systemically throughout the 24h period) and either bortezomib, (n=6; 0.4 mg/kg weekly IP), or rituximab, (n=13; 3 mg/kg, 2x weekly IP). Analysis of the OCI-Ly19 tumor volumes at day 46 showed a median of 2364 mm3 with bortezomib alone compared with 1823 mm3 with bortezomib and FosD. When FosD was combined with rituximab the most significant cytotoxicity was observed: (p=0.01; median tumor volume of 497 mm3 following the combination) in comparison to either FosD alone (3150 mm3) or rituximab alone (1764 mm3). We conclude that the addition of FosD appears to increase activity against NHL of several drugs, including fludarabine and rapamycin. These agents have significant activity in indolent and mantle cell NHL as well as CLL. Moreover, there is no evidence that FosD impedes rituximab responses in vitro or in vivo; in fact we have suggested possible synergy with the combination of rituximab and FosD. Based upon the documented single agent activity of FosD in humans, and this data, clinical trials are now indicated using these promising combinations in NHL and CLL. Disclosures: Pine: Rigel: Employment. Friedberg:Rigel: Research Funding.

scholarly journals Smoothened inhibition leads to decreased cell proliferation and suppressed tissue fibrosis in the development of benign prostatic hyperplasia

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Jianmin Liu ◽  
Jing Yin ◽  
Ping Chen ◽  
Daoquan Liu ◽  
Weixiang He ◽  
...  
Keyword(s):  
Benign Prostatic Hyperplasia ◽  
Control Point ◽  
Prostatic Hyperplasia ◽  
Common Disease ◽  
Tissue Fibrosis ◽  
Cycle Arrest ◽  
Promising Therapeutic Target ◽  
Human Solid Tumors

AbstractBenign prostatic hyperplasia (BPH) is a common disease in aging males. It has been proven that the Hedgehog (HH) is implied as an effective and fundamental regulatory growth factor signal for organogenesis, homeostasis, and regeneration. Smoothened (SMO), as the major control point of HH signals, activates aberrantly in most human solid tumors. However, the specific function of SMO and its downstream glioma-associated oncogene (GLI) family in BPH has not been well understood. Here, we first revealed that the SMO cascade was upregulated in BPH tissues and was localized in both the stromal and the epithelium compartments of human prostate tissues. Cyclopamine, as a specific SMO inhibitor, was incubated with BPH-1 and WPMY-1, and intraperitoneally injected into a BPH rat model established by castration with testosterone supplementation. SMO inhibition could induce cell apoptosis, cell cycle arrest at the G0/G1 phase, and a reduction of tissue fibrosis markers, both in vitro and in vivo. Finally, a tissue microarray, containing 104 BPH specimens, was constructed to analyze the correlations between the expression of SMO cascade and clinical parameters. The GLI2 was correlated positively with nocturia and negatively with fPSA. The GLI3 was in a positive relationship with International Prostate Symptom Score and nocturia. In conclusion, our study suggested that SMO cascade could play important roles in the development of BPH and it might be rediscovered as a promising therapeutic target for BPH.

scholarly journals Assortment of Stauntonia hexaphylla and Cornus officinalis protect against testosterone-induced benign prostatic hyperplasia through anti-inflammatory and anti-proliferative activity

2019 ◽  
Author(s):  
Shanika Karunasagara ◽  
Geum-Lan Hong ◽  
Da-Young Jung ◽  
Kyung-Hyun Kim ◽  
Eun-Jeong Koh ◽  
...  
Keyword(s):  
Benign Prostatic Hyperplasia ◽  
Western Blotting ◽  
Specific Antigen ◽  
Prostatic Hyperplasia ◽  
Nuclear Antigen ◽  
Control Group ◽  
Cornus Officinalis

AbstractBenign prostatic hyperplasia (BPH) is a progressive pathological condition associated with proliferation of prostatic tissues, prostate enlargement, and lower-urinary tract symptoms. However, the mechanism underlying the pathogenesis of BPH is not clear. The aim of this study was to investigate the protective effects of Stauntonia hexaphylla and Cornus officinalis (SC extract) on a testosterone propionate (TP)-induced BPH model. For in vitro experiments, a human prostate adenocarcinoma cell line was used to perform western blotting for androgen receptor (AR), prostate specific antigen (PSA), and 5α-reductase type 2. Male Sprague-Dawley rats were randomly divided into 8 groups as follows for the in vivo experiments: control, BPH, Fina, Saw, SC25, SC50, SC100, and SC200. To induce BPH, all rats, except those in the control group, were daily administered with subcutaneous injections of TP (5 mg/kg), and orally treated with appropriate PBS/drugs for 4 consecutive weeks. Our findings indicated that the SC treatment significantly reduced the prostate size and downregulated the serum testosterone and DHT levels in BPH rats. The histological examination revealed that SC treatment markedly recovered the TP-induced abnormalities and reduced the prostatic hyperplasia. In addition, in vitro and in vivo western blotting indicated that SC treatment significantly downregulated the AR, PSA, and 5α-reductase type 2 expression, while an immunohistochemistry examination revealed that the SC extract significantly reduced the expression of type 2 5α-reductase and proliferating cell nuclear antigen positive cell count. Collectively, our findings demonstrated that SC extract attenuates BPH through anti-proliferative and anti-inflammation activities and might be useful in the clinical treatment of BPH.

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