AUTHOR=Li Ren-shi , Xu Gong-hao , Cao Juan , Liu Bei , Xie Hai-feng , Ishii Yuji , Zhang Chao-feng 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.01305

DOI=10.3389/fphar.2019.01305

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Purpose:</bold> 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).</p><p><bold>Methods:</bold> Histopathological changes and collagen deposition were analyzed <italic>via</italic> 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.</p><p><bold>Results:</bold><italic>In vivo</italic> 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. <italic>In vitro</italic> 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.</p><p><bold>Conclusion:</bold> 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.</p>