Bryodulcosigenin attenuates bleomycin‐induced pulmonary fibrosis via inhibiting AMPK‐mediated mesenchymal epithelial transition and oxidative stress

Abstract

Fibrosis is a pathological result of a dysfunctional repair response to tissue injury and occurs in several organs, including the lungs. Bryodulcosigenin (BDG) is a cucurbitane‐type triterpene isolated from Siratia grosvenori and has clear‐cut anti‐inflammatory effects, yet its benefit of pulmonary fibrosis (PF) remains unclear. In this study, we investigated the protective effects of BDG (10 mg/kg/day, for 14 days) against TGF‐β1‐stimulated mouse alveolar epithelial MLE‐12 cells and bleomycin (BLM)‐induced PF mice. In vitro experiments showed that BDG could inhibit epithelial‐mesenchymal transition (EMT) and oxidative stress. In vivo experiments indicated that BDG could ameliorate BLM‐induced PF in mice as evidenced by characteristic structural changes in histopathology, increased collagen deposition and reduced survival and weight of mice. The abnormal increased expressions of TGF‐β1, p‐Smad2/3, α‐SMA, COL‐I, and NOX4 and decreased expressions for Sirt1 and p‐AMPK were improved in BDG treatment. But these beneficial effects could be eliminated by co‐treatment with Compound C (CC, a selective AMPK inhibitor). Molecular docking technology also revealed the potential of BDG to activate AMPK. In summary, AMPK activation modulated by BDG not only ameliorated TGF‐β1/Smad2/3 signaling pathways but also partially mediated the suppression effects on EMT and oxidative stress, thus mediating the anti‐fibrotic effects.

Preclinical evidence using synthetic compounds and natural products indicates that AMPK represents a potential pharmacological target for the therapy of pulmonary diseases

“…The AMPK/NOX4 pathway was involved in the inhibitory effect of Mogrol on TGF‐β1‐mediated fibroblasts proliferation and activation, ECM accumulation in primary mouse lung fibroblasts, and the protective effect of Mogrol toward bleomycin‐induced PF in mice 212 . The AMPK/NOX4 pathway was also involved in the inhibitory effect of Bryodulcosigenin (a natural product) on TGF‐β1‐induced EMT in MLE‐12 cells and the protective effect of Bryodulcosigenin toward bleomycin‐induced PF in mice 213 …”

Pharmacological Activities of Mogrol: Potential Phytochemical against Different Diseases

“…AMPK activation may be the important mechanism for mogrol activity; hence, molecular docking analysis was also conducted to study the interaction and binding energy of mogrol with AMPK, and mogrol had a slightly better docking score than AMP. Results from the study suggest the anti-fibrosis activity of mogrol results at least partly from the activation of AMPK [ 26 , 46 ].…”