Protective effects of Silibinin and cinnamic acid against paraquat-induced lung toxicity in rats: impact on oxidative stress, PI3K/AKT pathway and miR-193a signaling

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Abstract Purpose Levels of reactive oxygen species (ROS) are the primary determinants of pulmonary fibrosis. It was discovered that antioxidants can ameliorate pulmonary fibrosis caused by prolonged paraquat (PQ) exposure. However, research into the precise mechanisms by which antioxidants influence the signaling pathways implicated in pulmonary fibrosis induced by paraquat is still insufficient. This research utilized a rat model of pulmonary fibrosis induced by PQ to examine the impacts of Silibinin (Sil) and cinnamic acid (CA) on pulmonary fibrosis, with a specific focus on pro-fibrotic signalling pathways and ROS-related autophagy. Methods Lung injury induced by paraquat was demonstrated to be associated with oxidative stress and inflammation of the lungs, downregulated (miR-193a) and upregulated PI3K/AKT/mTOR signaling lung tissues. Expression levels of miR-193a were determined with quantitative real-time PCR, protein level of protein kinase B (Akt), phosphoinositide 3-Kinase (PI3K) were determined by western blot analysis. Hydroxyproline levels (HYP) and Transforming growth factor-β1 (TGF-β1) were measured by ELISA, malondialdehyde(MDA), total antioxidant capacity (TAO), glutathione peroxidase (GSH) and catalase and were measured in lung tissue homogenates colorimetrically using spectrophotometer. Results Long-term exposure to paraquat resulted in decreased PI3K/AKT signalling, decreased cell autophagy, increased oxidative stress, increased and helped pulmonary fibrosis formation. Silibinin and cinnamic acid also decreased oxidative stress by increasing autophagy and miR-193a expression, which in turn decreased pulmonary fibrosis. These effects were associated by low TGF- β1. Conclusions Silibinin and cinnamic acid inhibited PQ-induced PI3K/AKT by stimulating miR-193-a expression, thus attenuating PQ- induced pulmonary fibrosis.

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