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

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.

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The role of G-protein-coupled membrane estrogen receptor in mouse Leydig cell function—in vivo and in vitro evaluation

Cell and Tissue Research ◽

10.1007/s00441-018-2861-7 ◽

2018 ◽

Vol 374 (2) ◽

pp. 389-412 ◽

Cited By ~ 13

Author(s):

M. Kotula-Balak ◽

P. Pawlicki ◽

A. Milon ◽

W. Tworzydlo ◽

M. Sekula ◽

...

Keyword(s):

Estrogen Receptor ◽

G Protein ◽

Leydig Cell ◽

Cell Function ◽

G Protein Coupled ◽

Mouse Leydig Cell ◽

Leydig Cell Function

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The activation of G protein-coupled receptor 30 (GPR30) inhibits proliferation of estrogen receptor-negative breast cancer cells in vitro and in vivo

Cell Death and Disease ◽

10.1038/cddis.2014.398 ◽

2014 ◽

Vol 5 (10) ◽

pp. e1428-e1428 ◽

Cited By ~ 64

Author(s):

W Wei ◽

Z-J Chen ◽

K-S Zhang ◽

X-L Yang ◽

Y-M Wu ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cancer Cells ◽

G Protein ◽

Breast Cancer Cells ◽

G Protein Coupled Receptor ◽

G Protein Coupled ◽

Estrogen Receptor Negative

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In vivo and in vitro evidence for ERβ regulation of G protein-coupled estrogen receptor (GPER) expression in normal women and those with endometriosis

Fertility and Sterility ◽

10.1016/j.fertnstert.2008.07.370 ◽

2008 ◽

Vol 90 ◽

pp. S161

Author(s):

B.J. Plante ◽

L. Yuan ◽

B. Lessey ◽

M.A. Fritz ◽

S.L. Young

Keyword(s):

Estrogen Receptor ◽

G Protein ◽

Normal Women ◽

G Protein Coupled

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Oleanolic Acid Ameliorates Benign Prostatic Hyperplasia by Regulating PCNA-Dependent Cell Cycle Progression In Vivo and In Vitro

Journal of Natural Products ◽

10.1021/acs.jnatprod.9b01210 ◽

2020 ◽

Vol 83 (4) ◽

pp. 1183-1189 ◽

Cited By ~ 3

Author(s):

Se-Yun Cheon ◽

Bo-Ram Jin ◽

Hyo-Jung Kim ◽

Hyo-Jin An

Keyword(s):

Cell Cycle ◽

Benign Prostatic Hyperplasia ◽

Oleanolic Acid ◽

Cell Cycle Progression ◽

Prostatic Hyperplasia ◽

Cycle Progression ◽

Dependent Cell

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6′-Sialyllactose Ameliorates in Vivo and in Vitro Benign Prostatic Hyperplasia by Regulating the E2F1/pRb–AR Pathway

Nutrients ◽

10.3390/nu11092203 ◽

2019 ◽

Vol 11 (9) ◽

pp. 2203 ◽

Cited By ~ 2

Author(s):

Jin ◽

Kim ◽

Chung ◽

Ha ◽

...

Keyword(s):

Cell Cycle ◽

Benign Prostatic Hyperplasia ◽

Specific Antigen ◽

Prostatic Hyperplasia ◽

Control Group ◽

Therapeutic Effects ◽

Cell Cycle Protein ◽

Wide Range

Abstract: Background: 6′-Sialyllactose (6SL) displays a wide range of the bioactive benefits, such as anti-proliferative and anti-angiogenic activities. However, the therapeutic effects of 6SL on benign prostatic hyperplasia (BPH) remain unknown. Methods: Six-week-old male Wistar rats (n = 40) were used for in vivo experiments. All rats were castrated and experimental BPH was induced in castrated rats by intramuscular injection of testosterone, with the exception of those in the control group. Rats with BPH were administrated finasteride and 0.5 or 1.0 mg/kg 6SL. Furthermore, the inhibitory effects of 6SL on human epithelial BPH cell line (BPH-1) cells were determined in vitro. Results: Rats with BPH exhibited outstanding BPH manifestations, including prostate enlargement, histological alterations, and increased prostate-specific antigen (PSA) levels. Compared to those in the BPH group, rats in the 6SL group showed fewer pathological changes and normal androgen events, followed by restoration of retinoblastoma protein (pRb) and cell cycle-related proteins. In BPH-1 cells, treatment with 6SL significantly suppressed the effects on the androgen receptor (AR), PSA, and E2F transcription factor 1 (E2F1)-dependent cell cycle protein expression. Conclusions: 6SL demonstrated anti-proliferative effects in a testosterone-induced BPH rat model and on BPH-1 cells by regulating the pRB/E2F1–AR pathway. According to our results, we suggest that 6SL may be considered a potential agent for the treatment of BPH.

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Protective Effect of Genistein against Compound 48/80 Induced Anaphylactoid Shock via Inhibiting MAS Related G Protein-Coupled Receptor X2 (MRGPRX2)

Molecules ◽

10.3390/molecules25051028 ◽

2020 ◽

Vol 25 (5) ◽

pp. 1028 ◽

Cited By ~ 2

Author(s):

Mukesh Kumar ◽

Kailash Singh ◽

Karthi Duraisamy ◽

Ahmed A. Allam ◽

Jamaan Ajarem ◽

...

Keyword(s):

G Protein ◽

Inhibitory Activity ◽

Cell Activation ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Mast Cell Activation ◽

Anaphylactoid Shock ◽

G Protein Coupled

Anaphylactoid shock is a fatal hypersensitivity response caused by non-IgE mediated mast cell activation. These reactions are mediated by a family of G protein-coupled receptors (GPCRs) known as Mas related GPCRX2 (MRGPRX2). Several US FDA approved drugs which are used in day to day life have been reported to cause anaphylactoid shock. Surprisingly, no therapeutic drugs are available which can directly target MRGPRX2 for treatment of anaphylactoid shock. Genistein is a non-steroidal polyphenol known for its diverse physiological and pharmacological activities. In recent studies, Genistein has been reported for its anti-inflammatory activity on mast cells. However, the effects and mechanistic pathways of Genistein on anaphylactoid reaction remain unknown. In the present study, we designed a battery of in-vitro, in-silico and in-vivo experiments to evaluate the anti-anaphylactoid activity of Genistein in order to understand the possible molecular mechanisms of its action. The in-vitro results demonstrated the inhibitory activity of Genistein on MRGPRX2 activation. Further, a mouse model of anaphylactoid shock was used to evaluate the inhibitory activity of Genistein on blood vessel leakage and hind paw edema. Taken together, our findings have demonstrated a therapeutic potential of Genistein as a lead compound in the treatment of anaphylactoid shock via MRGPRX2.

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Studies of involvement of G-protein coupled receptor-3 in cannabidiol effects on inflammatory responses of mouse primary astrocytes and microglia

PLoS ONE ◽

10.1371/journal.pone.0251677 ◽

2021 ◽

Vol 16 (5) ◽

pp. e0251677

Author(s):

Jun Wu ◽

Nu Chen ◽

Yongqing Liu ◽

Grzegorz Godlewski ◽

Henry J. Kaplan ◽

...

Keyword(s):

G Protein ◽

Glial Cells ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

G Protein Coupled Receptor ◽

Primary Astrocytes ◽

Anti Inflammatory ◽

G Protein Coupled

Cannabidiol (CBD) exhibits anti-inflammatory and neuroprotective properties and is suggested to be effective in the pre-clinical and clinical treatment of illnesses of the central nervous system (CNS). Two major types of CNS glial cells, astrocytes and microglia, play critical roles in the development and pathogenesis of CNS diseases. However, the mechanisms by which CBD plays an anti-inflammatory and neuroprotective role for these glial cells have not been fully elucidated. In this study, we examined the effects of CBD on the inflammatory response of mouse primary astrocytes and microglia. We also investigated whether the effect of CBD on cytokine release is mediated by the G protein coupled receptor 3 (GPR3), which was recently identified as a novel receptor for CBD. Our results showed that CBD inhibited inflammatory responses of astrocytes and microglia stimulated with lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) ligand in vitro and in vivo. In addition, CBD reduced the phosphorylation of STAT3 and NF-κB signaling pathways in LPS-stimulated astrocytes. However, the inhibitory effect of CBD on pro-inflammatory cytokine production was independent of GPR3 expression in both types of glial cells. Thus, although CBD is effective in ameliorating the activation of astrocytes and microglia, its mechanism of action still requires further study. Our data support the concept that CBD may have therapeutic potential for neurological disorders that involve neuroinflammation.

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