4-Methylcoumarin-[5, 6–g]-hesperetin attenuates inflammatory responses in alcoholic hepatitis through PPAR-γ activation. (1st June 2019)

• Record Type: Journal Article
• Authors: Meng, Hong-Wu; You, Hong-Mei; Yang, Yang; Zhang, Yi-Long; Meng, Xiao-Ming; Ma, Tao-Tao; Huang, Cheng; Li, Jun
• Is Part Of: Toxicology. Volume 421(2019)
• Page Start: 9
• Page End: 21
• Publication Date: 2019-06-01
• Subjects: AH alcoholic hepatitis -- 4-MCH 4-Methylcoumarin-[56-g]-hesperetin -- PPAR-γ peroxisome proliferator-activated receptor-γ -- TNF-α tumor necrosis factor-α -- IL-6 interleukin-6 -- MTT methyl thiazolyl tetrazolium -- ALT alanine aminotransferase -- AST aspartate aminotransferase; Alcoholic hepatitis -- 4-Methylcoumarin-[5, 6-g]-hesperetin -- Inflammatory response -- PPAR-γ -- NF-κB-p65; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2019.04.004
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: 4-MCH acts as a PPAR-γ activator to alleviate inflammatory response via NF-κB-p65 signaling pathway in AH. 4-MCH plays an important anti-inflammatory role in the alcoholic liver disease which up-regulated the expression of PPAR-γ resulting in suppressed phosphorylation of p65. The selective inhibitor T0070907, PPAR-γ siRNA and pEX-2- PPAR-γ were put into use to demonstrate the potential mechanism of 4-MCH in preventing the release of inflammatory cytokines IL-6 and TNF-α. All the results suggest that 4-MCH should be developed as a new candidate for treating alcoholic hepatitis. Highlights: 4-MCH, a new synthesized compound in our laboratory. Remarkably inhibited inflammatory response in alcoholic hepatitis by treating with 4-MCH. The anti-inflammation property of 4-MCH in vivo and in vitro . Potential pharmacological mechanism of 4-MCH administration in AH. 4-MCH may be an effective candidate for AH. Abstract: 4-Methylcoumarin-[5, 6– g ]-hesperetin (4-MCH) is a hesperidin derivative produced by the structural modification of hesperetin. Alcoholic hepatitis (AH) is the origin of many serious liver diseases that are accompanied by hepatic inflammation. In this study, we detected the anti-inflammatory activity of 4-MCH in EtOH fed mice and examined the potential molecular mechanism of this activity. We found that 4-MCH suppressed the release of inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in primary liver macrophages isolated from mice and in EtOH-treated RAW264.7 cells. In addition, we showed that the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ) was down-regulated in vivo and in vitro in AH. Furthermore, 4-MCH acted as an activator of PPAR-γ, which could therefore ameliorate the inhibitory effects of EtOH on the expression of PPAR-γ. The impairment of PPAR-γ function (T0070907 or PPAR-γ siRNA treatment) resulted in greater inflammation than that in the control group. Conversely, over-expression of PPAR-γ further reduced the release of inflammatory cytokines from EtOH-stimulated RAW264.7 cells. Additional investigations showed that 4-MCH significantly inhibited the phosphorylation of p65. Collectively, these results indicate that 4-MCH alleviated the inflammatory reaction through PPAR-γ activation via the NF-κB-p65 signaling pathway, which regulates the expression of IL-6 and TNF-α in AH.