Palmitoylethanolamide/Baicalein Regulates the Androgen Receptor Signaling and NF-κB/Nrf2 Pathways in Benign Prostatic Hyperplasia

Abstract

Benign prostatic hyperplasia (BPH) is the most common benign tumor in males. Androgen/androgen receptor (AR) signaling plays a key role in the development of BPH; its alterations cause an imbalance between prostate cell growth and apoptosis. Furthermore, chronic inflammation and oxidative stress, which are common conditions in BPH, contribute to disrupting the homeostasis between cell proliferation and cell death. With this background in mind, we investigated the effect of ultramicronized palmitoylethanolamide (um-PEA), baicalein (Baic) and co-ultramicronized um-PEA/Baic in a fixed ratio of 10:1 in an experimental model of BPH. BPH was induced in rats by daily administration of testosterone propionate (3 mg/kg) for 14 days. Baic (1 mg/kg), um-PEA (9 mg/kg) and um-PEA/Baic (10 mg/kg) were administered orally every day for 14 days. This protocol led to alterations in prostate morphology and increased levels of dihydrotestosterone (DHT) and of androgen receptor and 5α-reductase expression. Moreover, testosterone injections induced a significant increase in markers of inflammation, apoptosis and oxidative stress. Our results show that um-PEA/Baic is capable of decreasing prostate weight and DHT production in BPH-induced rats, as well as being able to modulate apoptotic and inflammatory pathways and oxidative stress. These effects were most likely related to the synergy between the anti-inflammatory properties of um-PEA and the antioxidant effects of Baic. These results support the view that um-PEA/Baic should be further studied as a potent candidate for the management of BPH.

Probenecid ameliorates testosterone‐induced benign prostatic hyperplasia: Implications of PGE‐2 on ADAM‐17/EGFR/ERK1/2 signaling cascade

“…In this study, elevated PW and PI, in the presence of TST, agree with the previous findings. [ 33,58,66–68 ] These findings may help us to better understand the correlation between TST and prostate enlargement in the elderly. This discrepancy could be attributed to the coexistence of multiple clinical disorders associated with high levels of inflammatory cytokines and oxidative stress in the elderly.…”

“…Notably, prostatic inflammation is one of the hallmarks of BPH. [58,68] It is characterized by the high expression of COX-2 particularly in the smooth muscle cells and basal epithelial cells of the prostate. [13,14] COX-2 has been shown to induce the production of pro-inflammatory PGs in the chronic inflammation of BPH, allowing cellular proliferation of prostate cells.…”

Origanum majorana L. Extract Attenuated Benign Prostatic Hyperplasia in Rat Model: Effect on Oxidative Stress, Apoptosis, and Proliferation

“…In BPH, Nrf2 and its target genes have been found to be deficient and insufficient for antioxidant response [ 67 ]. Nrf2 regulates the expression of key protective elements in BPH [ 68 ]. On the other hand, activation of Nrf2 blocks TGF-β signaling and suppresses inflammation, thereby restraining prostatic epithelial-mesenchymal transition in BPH [ 69 ].…”

Cyclooxygenase-2 activates EGFR–ERK1/2 pathway via PGE2-mediated ADAM-17 signaling in testosterone-induced benign prostatic hyperplasia

“…These results mirror those of the previous studies that have examined the dysregulation in pro-apoptotic Bax and anti-apoptotic Bcl-2 (Abdel-Naim et al 2018 ; Abo-Youssef et al 2020 ). Surprisingly, no differences were found when the protein levels of pro-apoptotic Bax and anti-apoptotic Bcl-2 were detected (Almukadi et al 2021 ; D’Amico et al 2021 ; Hsu et al 2021 ). This implies that the normal hemodynamic balance of the prostate may be disrupted and further directed toward hyperplasia.…”