AUTHOR=Wen Quan , Lau Ngaikeung , Weng Huandi , Ye Peng , Du Shaohui , Li Chun , Lv Jianping , Li Hui 

TITLE=Chrysophanol Exerts Anti-inflammatory Activity by Targeting Histone Deacetylase 3 Through the High Mobility Group Protein 1-Nuclear Transcription Factor-Kappa B Signaling Pathway in vivo and in vitro

JOURNAL=Frontiers in Bioengineering and Biotechnology

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/bioengineering-and-biotechnology/articles/10.3389/fbioe.2020.623866

DOI=10.3389/fbioe.2020.623866

ISSN=2296-4185

ABSTRACT=<p>Chrysophanol (Chr) is the main monomer isolated from <italic>Rheum rhabarbarum</italic>. This study aimed to identify the potential <italic>in vitro</italic> and <italic>in vivo</italic> cytoprotective effects of Chr on lipopolysaccharide (LPS)-triggered acute lung injury (ALI). We used an ALI-murine model and constructed an inflammatory macrophage <italic>in vitro</italic> cell model to determine the cellular mechanisms involved in Chr-mediated activity. To observe the vital role of histone deacetylase 3 (HDAC3) in abolishing inflammation action, HDAC3 was downregulated using small interfering RNA. Analysis of the expression of nuclear transcription factor-kappa B p65 (NF-κB p65) and molecules of its downstream signaling pathway were assessed <italic>in vitro</italic> and in lung tissue samples using the mouse model. Concentrations of tumor necrosis factor-α, interleukin-1β, high mobility group protein 1 (HMGB1), and interleukin-16 in supernatants and the bronchoalveolar lavage fluid were measured using enzyme-linked immunosorbent assay. A reporter gene assay measured HMGB1 activity, and NF-κB p65 and HMGB1 intracellular localization was determined by immunofluorescence detection on histological lung samples from Chr-treated mice. The protein interactions between HMGB1, HDAC3, and NF-κB p65 were tested by co-immunoprecipitation. Chr treatment relieved LPS-induced lung lesions. Chr also enhanced superoxide dismutase levels in ALI mice. Chr reduced the LPS-induced protein expression of NF-κB and its related pathway molecules in both <italic>in vivo</italic> and <italic>in vitro</italic> models. Moreover, Chr downregulated LPS-enhanced HMGB1 expression, acetylation, and nuclear nucleocytoplasmic translocation. However, HDAC3 knockdown substantially reduced Chr-mediated HDAC3/NF-κB expression.</p><p>Furthermore, Chr enhanced HMGB1/HDAC3/NF-κB p65 complex interaction, whereas HDAC3 knockdown reduced Chr-mediated HMGB1/HDAC3/NF-κB p65 formation. This study showed that the protective effects induced by Chr were associated with the regulation of the HMGB1/NF-κB pathway via HDAC3.</p>