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

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 char-acteristics were evaluated. Prostate weight, prostate index (prostate/body weight ratio), expression of type II 5a-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-b1, TGF-b 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 lM neferine with 1 lM testosterone or 10 nM TGF-b1 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 transi-tion (EMT). Moreover, TGF-b1, TGFBR2 and p-Smad2/3, N-cadherin and vimentin expression were increased but E-cadherin was decreased after 24 h TGF-b1 treatment in WPMY-1 cells. Neferine reversed the effects of TGF-b1 treatment in WPMY-1 cells. Neferine appeared to suppress prostate growth by reg-ulating the EMT, AR and TGF-b/Smad signaling pathways in the prostate and is suggested as a potential agent for BPH treatment.& COPY; 2023 The Author(s). Published by Elsevier B.V. on behalf of King Saud University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).