Dibutyl phthalate‐induced oxidative stress and apoptosis in swine testis cells and therapy of naringenin via PTEN/PI3K/AKT signaling pathway

Abstract

Dibutyl phthalate (DBP) is a phthalic acid ester (PAE) that has posed a health hazard to the organisms. Naringenin (NRG) is a flavanone compound that has shown protection against several environmental chemicals through suppression of oxidative stress and activation of phosphatidylinositol 3-kinase/threonine kinase (PI3K/AKT) signaling pathway. Herein, swine testis (ST) cells were treated with 1.8 μM of DBP or/and 25.39 nM of NRG for 24 h, we described the discovery path of NRG inhibition on apoptosis in DBP-exposed ST cells through targeting phosphatase and tensin homologue deleted on chromosome 10 (PTEN). We first found that the anti-apoptosis effect of NRG is dependent on mitochondrial pathway through flow cytometry and related gene/protein expression, and then we detected PI3K/AKT pathway-related gene/protein expression, and established a computational docking assay between NRG and PTEN. We found that NRG specifically binds to three basic residues (His93, Lys125, Lys128) of P loop in PTEN, as well as phosphatase domains (Asp92, His93, Cys124, Lys125, Ala126, Lys128, and Arg130) in active dephosphorylation pockets, thereby reducing PTEN level and activating PI3K/AKT signaling pathway, and further inhibiting oxidative stress and mitochondrial pathway apoptosis. Taken together, our results push forward that NRG deserves further attention as a potential antagonistic therapy against DBP through targeting PTEN to inhibit oxidative stress and activate PI3K/AKT signaling pathway.

Research progress on anti-stress nutrition strategies in swine

“…For signaling pathways, signaling molecules in the Kelch-like epichlorohydrin-associated protein 1 (Keap1)/Nrf2 signaling pathway ( Costilla et al., 2019 ; Zhou et al., 2020b ), NF-κB ( Kianian et al., 2022 ), mitogen-activated protein kinase (MAPK) ( Lee et al., 2020 ), AMP-activated protein kinase (AMPK) ( Yang et al., 2018a , 2018b ) and PTEN/phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) ( Chen et al., 2022a ; Sun et al., 2022 ) pathways have been verified to modulate the expression of relevant redox genes to alleviate or activate stress progression in swine ( Hao et al., 2021 ). Nrf2 binds to the antioxidant response element to upregulate the expression of genes encoding phase II detoxification or antioxidant enzymes ( Itoh et al., 1997 ; Motohashi et al., 2004 ; Cho et al., 2006 ; Hyeon et al., 2013 ).…”