ABSTRACT
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.
Subject(s)
4-Butyrolactone/analogs & derivatives , Antineoplastic Agents, Phytogenic/metabolism , Butylene Glycols/metabolism , Flax/chemistry , Glucosides/metabolism , Lignans/metabolism , Models, Molecular , Prostatic Hyperplasia/metabolism , Receptors, G-Protein-Coupled/agonists , 4-Butyrolactone/chemistry , 4-Butyrolactone/metabolism , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/therapeutic use , Binding Sites , Butylene Glycols/chemistry , Butylene Glycols/therapeutic use , Cell Line, Tumor , Cell Proliferation , Dietary Supplements , Gene Expression Regulation, Neoplastic , Glucosides/chemistry , Glucosides/therapeutic use , Glycosides/chemistry , Glycosides/metabolism , Glycosides/therapeutic use , Humans , Lignans/chemistry , Lignans/therapeutic use , Male , Molecular Docking Simulation , Neoplasm Proteins/agonists , Neoplasm Proteins/chemistry , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Prostate/metabolism , Prostate/pathology , Prostatic Hyperplasia/diet therapy , Prostatic Hyperplasia/pathology , RNA Interference , Random Allocation , Rats , Rats, Wistar , Receptors, Estrogen/chemistry , Receptors, Estrogen/genetics , Receptors, Estrogen/metabolism , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Seeds/chemistryABSTRACT
Functional food-flaxseed and its derivatives (flaxseed oil or lignans) are beneficial for human health, possibly because of their anti-inflammatory effects. C-reactive protein (CRP), a sensitive marker of inflammation was chosen to evaluate the anti-inflammatory effects of flaxseed. We searched randomized controlled trials from PubMed and the Cochrane Library in October 2015 and conducted a meta-analysis to evaluate the effectiveness of flaxseed and its derivatives on CRP. The mean differences (net change) in CRP (mg/L) concentrations were pooled with a random- or a fixed-effects model depending on the results of heterogeneity tests. Overall, flaxseed interventions had no effects on reduction of CRP (p = 0.428). The null effects were consistent in the subgroup analysis with multiple studies and population characteristics. Significant heterogeneity was observed in most of the analyses. Meta-regression identified baseline body mass index (BMI) as a significant source of heterogeneity (P-interaction = 0.032), with a significant reduction in CRP of 0.83 mg/L (95% confidence interval -1.34 to -0.31; p = 0.002) among subjects with a BMI of ≥30 kg/m². In conclusion, our meta-analysis did not find sufficient evidence that flaxseed and its derivatives have a beneficial effect on reducing circulating CRP. However, they may significantly reduce CRP in obese populations.