O-alkyl and o-benzyl hesperetin derivative-1L attenuates inflammation and protects against alcoholic liver injury via inhibition of BRD2-NF-κB signaling pathway. (30th January 2022)

• Record Type: Journal Article
• Authors: Li, Juan-Juan; Lu, Xin-Yi; Jia, Pengcheng; Zhu, Lin; Wang, Ao; Bu, Fang-Tian; Zhang, Yi-Long; Huang, Cheng; Li, Jun
• Is Part Of: Toxicology. Volume 466(2022)
• Publication Date: 2022-01-30
• Subjects: Alcoholic liver injury -- Bromodomain-containing protein 2 -- O-alkyl and o-benzyl hesperetin derivative-1L -- Inflammation -- NF-κB; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2021.153087
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: A schematic model of O-alkyl and o-benzyl hesperitin derivative-1L ameliorates alcoholic liver injury by inhibiting BRD2-NF-κB signaling pathway. Therefore, HD-1L is a potential treatment option for inhibiting liver inflammation and the progression of Alcoholic liver diseases. Highlights: HD-1L, a new compound synthesized in our laboratory. HD-1L alleviates liver injury in alcohol-induced liver injury mice. HD-1L attenuates the inflammatory response in vivo and in vitro . Potential pharmacological mechanism of HD-1L administration in ALI. HD-1L may be a valid candidate for ALI. Abstract: Alcoholic liver injury (ALI) is a major risk factor for alcoholic liver disease, characterized by excessive inflammatory response and abnormal liver dysfunction. Previous studies have indicated that O-alkyl and o-benzyl hesperetin derivative-1 L (HD-1 L) has anti-inflammatory and hepato-protective effects in CCl4 -induced liver injury. However, its effect on ALI and underlying mechanism has not been elucidated. This study was designed to evaluate the protective effects of HD-1 L on alcoholic liver injury and reveal the underlying mechanisms. ALI model was established in male C57BL/6 J mice (aged 6–8 weeks) by Gao-Binge protocol. The mice were received different doses of HD-1 L (25 mg/kg, 50 mg/kg, 100 mg/kg) by daily intragastric administration, respectively. Liver function and inflammation were measured. Mechanism underlying the anti-inflammatory and hepato-protective effect of HD-1 L were studied in RAW264.7 cells. In alcoholic liver injury mice, HD-1 L effectively improved the liver pathology, and remarkably reduced the levels of alanine transaminase (ALT), aspartate transaminase (AST), triglyceride (TG) and total cholesterol (T-CHO) in serum. Moreover, HD-1 L markedly suppressed inflammation in vivo and inhibited the secretion of inflammatory factors in vitro . Our results showed that HD-1 L decreased the activity of Bromodomain-containing Protein 2 (BRD2) and inhibited expression of BRD2 in vivo and in vitro . Furthermore, HD-1 L further alleviated alcohol-induced inflammation after blocking BRD2 with inhibitor (JQ1) or BRD2 small interfering (si)-RNA in RAW264.7 cells. Besides, HD-1 L failed to effectively exert its anti-inflammatory effects after over expression of BRD2. In addition, HD-1 L significantly inhibited the phosphorylation and activation of NF-κB-P65 mediated by BRD2. In conclusion, HD-1 L alleviated liver injury and inflammation mainly by inhibiting BRD2-NF-κB signaling pathway, and HD-1 L may be a potential anti-inflammatory compound in treatment of alcoholic liver disease.