Sinapic Acid Reduces Oxidative Stress and Pyroptosis via Inhibition of BRD4 in Alcoholic Liver Disease

Abstract

Alcoholic liver disease (ALD) is one of the main causes of death in chronic liver disease. Oxidative stress and pyroptosis are important factors leading to ALD. Bromodomain-containing protein 4 (BRD4) is a factor that we have confirmed to regulate ALD. As a phenolic acid compound, sinapic acid (SA) has significant effects in antioxidant, anti-inflammatory and liver protection. In this study, we explored whether SA regulates oxidative stress and pyroptosis through BRD4 to play a protective effect in ALD. Male C57BL/6 mice and AML-12 cells were used for experiments. We found that SA treatment largely abolished the up-regulation of BRD4 and key proteins of the canonical pyroptosis signalling in the liver of mice fed with alcohol, while conversely enhanced the antioxidant response. Consistantly, both SA pretreatment and BRD4 knockdown inhibited oxidative stress, pyroptosis, and liver cell damage in vitro. More importantly, the expression levels of BRD4 and pyroptosis indicators increased significantly in ALD patients. Molecule docking analysis revealed a potent binding of SA with BRD4. In conclusion, this study demonstrates that SA reduces ALD through BRD4, which is a valuable lead compound that prevents the ALD process.

Syringic Acid Ameliorates Cardiac, Hepatic, Renal and Neuronal Damage Induced by Chronic Hyperglycaemia in Wistar Rats: A Behavioural, Biochemical and Histological Analysis

“…Consistent with our findings, SA has prevented isoproterenol-induced cardiac hypertrophy in rats [ 56 ]. No reports currently exist on the effect of SA on diabetes-induced renal and hepatic hypertrophy, but the parent group sinapic acid reversed renal hypertrophy in T1DM [ 139 ] and reduced relative hepatic weight in rats with chronic alcohol-induced liver injury and steatosis [ 140 ]. Thus, the mechanism of reducing hypertrophy could result in an improvement in dyslipidaemia, TGF-β1 inhibition, and anti-inflammatory and antioxidative effects.…”

Four Different Structural Dietary Polyphenols, Especially Dihydromyricetin, Possess Superior Protective Effect on Ethanol-Induced ICE-6 and AML-12 Cytotoxicity: The Role of CYP2E1 and Keap1-Nrf2 Pathways

“…Sinapic acid could alleviate alcohol-induced oxidative stress by activating the Nrf2 signaling pathway to upregulate the expression of downstream key antioxidant proteins HO-1 and SOD. 39 The polyphenols extracted from Zizania latifolia could protect mice with acute alcoholism by increasing the level of antioxidant enzymes in serum. 40 In this study, ethanol could significantly promote the depletion of GSH, SOD, and CAT in AML-12 cells, while promoting the accumulation of MDA and ROS, indicating that the antioxidant defense system of AML-12 cells was disrupted.…”

“…In previous studies, dietary polyphenols were found to have biological activities to maintain the body’s redox homeostasis. Sinapic acid could alleviate alcohol-induced oxidative stress by activating the Nrf2 signaling pathway to upregulate the expression of downstream key antioxidant proteins HO-1 and SOD . The polyphenols extracted from Zizania latifolia could protect mice with acute alcoholism by increasing the level of antioxidant enzymes in serum .…”

Regulation of programmed cell death by Brd4

“…Therefore, Brd4 appears to modulate the activation of different forms of inflammasome in response to distinct stimuli and the detailed molecular mechanisms merit further investigation (Fig. 4) [15,110,112,[116][117][118][119].…”