metallothionein and naringenin

Naringenin (Nar) is a flavanone that has been suggested to provide human health benefits such as anti-inflammatory, anti-oxidant and anti-cancer properties. However, the mechanisms underlying these benefits are complex and still not fully understood. In this study, we investigated the effect of Nar on the inflammatory response of macrophages and its underlying mechanism. In lipopolysaccharide (LPS)-stimulated human macrophages, Nar inhibited the activation of NF-κB pathway and suppressed the downstream expression of pro-inflammatory factors. In addition, Nar was also able to induce metallothionein 1 G (MT1G) expression, and the inhibitory effects of Nar on the production of pro-inflammatory cytokines was dependent on MT1G. Mechanistically, we found that MT1G-mediated inhibition of pro-inflammatory cytokines responses might be through repressing NF-κB activation via zinc chelation. Overall, this study reveals a novel mechanism of Nar on inflammatory responses, the suppression of NF-κB activation through upregulation of MT1G.

Topics: Anti-Inflammatory Agents; Antioxidants; Cells, Cultured; Cytokines; Flavanones; HEK293 Cells; Humans; Inflammation; Lipopolysaccharides; Macrophages; Metallothionein; NF-kappa B; Signal Transduction; THP-1 Cells; Up-Regulation

Naringenin is a natural flavonoid aglycone of naringin that has been reported to have a wide range of pharmacological properties, such as antioxidant activity and free radical scavenging capacity. This study was designed to examine the hepatoprotective effect of naringenin against acetaminophen (250 mg kg(-1), sc) in metallothionein (MT)-null mice. 42 SPF MT-knockout mice were used. Naringenin (200, 400, and 800 mg kg(-1), ig) was administered for 4 days before exposure to acetaminophen (250 mg kg(-1), sc). Liver injury was measured by serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), as well as liver malondialdehyde (MDA). The glutathione-to-oxidized glutathione ratio (GSH/GSSG) was also assessed. The evidence of liver injury induced by acetaminophen included not only a significant increase in the levels of serum ALT, AST, LDH and liver MDA, and also a significant decrease in GSH/GSSG. Pretreatment of mice with naringenin at 400 and 800 mg kg(-1) reversed the altered parameters. Such reversal effects were dose-dependent: ALT decreased 78.62% and 98.03%, AST decreased 88.35% and 92.64%, LDH decreased 76.54% and 81.63%, MDA decreased 48.59% and 66.27% at a dose of 400 and 800 mg kg(-1) respectively; GSH/GSSG increased 22.57% and 16.93% at a dose of 400 and 800 mg kg(-1) respectively. Histopathological observation findings were also consistent with these effects. Together, this study suggests that naringenin can potentially reverse the hepatotoxic damage of acetaminophen intoxication in MT-null mice.

Topics: Acetaminophen; Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Flavanones; Glutathione; Humans; Liver; Male; Malondialdehyde; Metallothionein; Mice; Mice, Knockout; Protective Agents