Alpha-Mangostin Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Mice Partly Through Activating Adenosine 5′-Monophosphate-Activated Protein Kinase

Abstract

Background: Pulmonary fibrosis (PF) is a devastating interstitial lung disease and characterized by an abnormal accumulation of extracellular matrix (ECM). Nintedanib (NDN) and pirfenidone are two approved therapies for PF, but their potential side-effects have been reported. Recently, the use of natural supplements for PF is attracting attention. Alpha-mangostin (α-MG) is an active xanthone-type compound isolated from the nutritious fruit mangosteen. Purpose: In the present study, the potential effect and underlying mechanism of α-MG were evaluated in bleomycin (BLM)-induced PF and activated primary lung fibroblasts (PLFs). Methods: Histopathological changes and collagen deposition were analyzed via hematoxylin-eosin staining and Masson staining, the expression of nicotinamide adenine dinucleotide phosphate oxidase-4 (NOX4) involved in oxidative stress in lung tissues was analyzed by immunochemistry staining. The expressions of α-smooth muscle actin (α-SMA), collagen I (Col I), p-adenosine 5′-monophosphate-activated protein kinase (AMPK)/AMPK, and NOX4 were detected by Western blot, immunofluorescence or RT-PCR, and effects of α-MG on cell viability were detected using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide. Results: In vivo results demonstrated that α-MG treatment (10 mg/kg/day) significantly ameliorated BLM-induced deposition of ECM in lung tissues. Moreover, α-MG could inhibit protein expressions of α-SMA and Col I as well as its mRNA levels. In addition, α-MG also significantly inhibited transforming growth factor-β1/Smad2/3 pathway and regulated the protein expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in lung tissues. In vitro results demonstrated that α-MG significantly increased p-AMPK/AMPK but reduced the protein expression level of α-SMA and Col I as well as NOX4 in activated PLFs. Further study demonstrated that these improvement effects were significantly blocked by compound C. Conclusion: α-MG treatment significantly decreased oxidative stress in lungs partly by activating AMPK mediated signaling pathway in BLM-induced PF and activated PLFs and decreased the deposition of ECM. The present study provides pharmacological evidence to support therapeutic application of α-MG in the treatment of PF.

Fisetin Alleviated Bleomycin-Induced Pulmonary Fibrosis Partly by Rescuing Alveolar Epithelial Cells From Senescence

“…After intra-tracheal instillation of BLM, significant weight loss, survival rate reduction and increased wet/dry weight ratio of lung were noticed ( Figures 1A–C ). The seventh day after BLM administration is considered to be the beginning of the fibrotic phase ( Li et al, 2019 ), FIS was intragastrically administered at day 7 for 21 days. BLM-induced weight loss and the increase in the wet/dry weight ratio were attenuated by FIS administration.…”

“…Massive collagen secreted by myofibroblasts is the major source of ECM, while α -SMA is a biomarker protein of myofibroblasts ( Li et al, 2019 ). HYP is one of the main components of collagen.…”

Alpha Mangostin Derived from <i>Garcinia magostana</i> Linn Ameliorates Cardiomyocyte Hypertrophy and Fibroblast Phenotypes <i>in Vitro</i>

“…26) Similarly, our data showed that α-man inhibited TGF-β-induced myofibroblast differentiation in cultured cardiac fibroblasts Periostin reportedly plays an important role in promoting collagen fibrogenesis and its overexpression has been observed in several heart diseases beside to HF. 27) Other researchers have described the protective effect of α-man on pulmonary and liver fibrosis, demonstrated through the reduced expression α-SMA, a myofibroblast marker protein. 28,29) The present study demonstrated the therapeutic effect of α-man in attenuating myofibroblast differentiation through thesuppression of α-SMA expression at both mRNA and protein levels in cultured cardiac fibroblasts.…”

Natural Product-Based Potential Therapeutic Interventions of Pulmonary Fibrosis

“…α-MG treatments also reduced the abnormal expression of TGF-β1 and the phosphorylation of Smad 2/3 in the lungs. Moreover, α-MG alleviates the process of fibrogenesis by promoting AMPK-mediated inhibition of NOX4 expression and TGF-β1-induced trans-differentiation of lung fibroblast [ 157 ].…”