Diterpenoid alkaloids isolated from Delphinium trichophorum alleviate pulmonary fibrosis via the TGF-β/Smad pathway in 3T6 and HFL-1 cells

• DOI: 10.1016/j.biopha.2022.112906
• Publication Date: 2022-04-04T21:12:17Z
• Authors: Yufeng Yao; Yuanyuan Chen; Dawa Zeren; Yunxia Ma; Yuanyuan Xie; Qian Wang; Huanhuan Ma; Meiqi Wang; Fangle Liu; Chenchen Zhu; Chaozhan Lin
• Keywords: Hydroxyproline

Delphinium trichophorum Franch (DTF), a species endemic to China, has been widely used for centuries in Tibet as an indigenous medicine treating cough, pneumonia, and pulmonary fibrosis. Hetisine-type C20-diterpenoid alkaloids have reported be characteristic active ingredients. Herein, five ones with relatively high contents D. trichophorum, including 2α,11α,13β-triacetylhetisine (DTF1), trichodelphinine A (DTF2), D (DTF3), 2α-acetyl-11α,13β-dihydroxyhetisine (DTF4), C (DTF5), were investigated anti-fibrosis effects using fibroblasts induced by TGF-β1 or LPS the first time. The results showed that all tested compounds decreased hydroxyproline (HYP) levels inhibited abnormal proliferation of 3T6 HFL-1 cells either LPS. Moreover, DTF1 DTF2 attenuated production collagen (Col-1 Col-3) at low doses, suggesting their higher efficiency among alkaloids. Based on large-scale ligand-based pharmacophore modeling, TGFBR1 was screened potential target these molecular docking also exhibited high-affinity interactions between alkaloids, especially DTF2. Further experiments revealed could inhibit expression α-SMA phosphorylation Smad3 Smad4 while restoring Smad7 protein. Overall, may reduce generation delay development fibrosis inhibiting activation TGF-β/Smad signaling pathway. Our provide experimental theoretical evidence superior candidates further anti-fibrotic drugs.