Neferine attenuates development of testosterone-induced benign prostatic hyperplasia in mice by regulating androgen and TGF-β/Smad signaling pathways

Chi-Ming Liu; ZiChen Shao; XuZhou Chen; HanWu Chen; MengQiao Su; ZiWen Zhang; ZhengPing Wu; Peng Zhang; LiJie An; YinJie Jiang; Ai-Jun Ouyang

doi:10.1016/j.jsps.2023.05.004

Neferine attenuates development of testosterone-induced benign prostatic hyperplasia in mice by regulating androgen and TGF-β/Smad signaling pathways

Saudi Pharm J. 2023 Jul;31(7):1219-1228. doi: 10.1016/j.jsps.2023.05.004. Epub 2023 May 11.

Authors

Chi-Ming Liu¹, ZiChen Shao^{1

2}, XuZhou Chen¹, HanWu Chen¹, MengQiao Su^{1

2}, ZiWen Zhang¹, ZhengPing Wu³, Peng Zhang¹, LiJie An^{1

2}, YinJie Jiang¹, Ai-Jun Ouyang⁴

Affiliations

¹ School of Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China.
² College of Chemistry and Bio-engineering, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China.
³ School of Aesthetic Medicine, Yichun University, 576 XueFu Road, Yuanzhou District, Yichun 336000, Jiangxi Province, China.
⁴ Department of Pharmacy, The First Affiliated Hospital of Nanchang University, 17 Yongwaizheng Street, Nanchang 330006, Jiangxi Province, China.

Abstract

Benign prostatic hyperplasia (BPH) is a common urinary disease among the elderly, characterized by abnormal prostatic cell proliferation. Neferine is a dibenzyl isoquinoline alkaloid extracted from Nelumbo nucifera and has antioxidant, anti-inflammatory and anti-prostate cancer effects. The beneficial therapeutic effects and mechanism of action of neferine in BPH remain unclear. A mouse model of BPH was generated by subcutaneous injection of 7.5 mg/kg testosterone propionate (TP) and 2 or 5 mg/kg neferine was given orally for 14 or 28 days. Pathological and morphological characteristics were evaluated. Prostate weight, prostate index (prostate/body weight ratio), expression of type Ⅱ 5α-reductase, androgen receptor (AR) and prostate specific antigen were all decreased in prostate tissue of BPH mice after administration of neferine. Neferine also downregulated the expression of pro-caspase-3, uncleaved PARP, TGF-β1, TGF-β receptor Ⅱ (TGFBR2), p-Smad2/3, N-cadherin and vimentin. Expression of E-cadherin, cleaved PARP and cleaved caspase-3 was increased by neferine treatment. 1-100 μM neferine with 1 μM testosterone or 10 nM TGF-β1 were added to the culture medium of the normal human prostate stroma cell line, WPMY-1, for 24 h or 48 h. Neferine inhibited cell growth and production of reactive oxygen species (ROS) in testosterone-treated WPMY-1 cells and regulated the expression of androgen signaling pathway proteins and those related to epithelial-mesenchymal transition (EMT). Moreover, TGF-β1, TGFBR2 and p-Smad2/3, N-cadherin and vimentin expression were increased but E-cadherin was decreased after 24 h TGF-β1 treatment in WPMY-1 cells. Neferine reversed the effects of TGF-β1 treatment in WPMY-1 cells. Neferine appeared to suppress prostate growth by regulating the EMT, AR and TGF-β/Smad signaling pathways in the prostate and is suggested as a potential agent for BPH treatment.

Keywords: Androgen receptor (AR); Apoptosis; Benign prostatic hyperplasia (BPH); Epithelial-mesenchymal transition (EMT); Neferine; TGF-β/Smad.