methyl-ferulate and Liver-Diseases--Alcoholic

A previous study indicated that microRNA-378b (miR-378b) plays a critical role in controlling hepatic insulin resistance by targeting insulin receptor (IR) and p110α in alcoholic liver disease (ALD). Methyl ferulic acid (MFA), a bioactive ingredient in Securidaca inappendiculata Hassk rhizomes, exhibits multiple pharmacological activities. It has been reported that MFA ameliorates insulin resistance in ALD, whereas the underlying molecular mechanism remains unclear. The objective of study was to evaluate the influence of MFA on insulin sensitivity in ethanol-induced L-02 cells as well as alcohol-fed mice and illuminate the function of miR-378b-mediated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway in system. MFA was found to remarkably down-regulate miR-378b level and increase IR and p110α expressions. Furthermore, the effect of MFA on modulating miR-378b/PI3K-AKT pathway to enhance insulin sensitivity was corroborated by overexpressing and inhibiting miR-378b. Taken together, MFA exhibited a positive effect against ALD by attenuating the inhibition of miR-378b on IR/p110α and partly activating the insulin signaling to alleviate alcohol-induced hepatic insulin resistance.

Topics: Animals; Caffeic Acids; Class I Phosphatidylinositol 3-Kinases; Gene Expression Regulation; Insulin Resistance; Liver Diseases, Alcoholic; Mice; MicroRNAs; Phosphatidylinositol 3-Kinase; Phytochemicals; Proto-Oncogene Proteins c-akt; Receptor, Insulin; Securidaca; Signal Transduction; Up-Regulation

The present study aimed to investigate the hepatoprotective effects of Methyl ferulic acid (MFA) against oxidative stress and apoptosis as well as inflammation in mice with liver injury induced by alcohol and its underlying mechanisms.. C57BL/6 mice were divided into a control group,a model group, and Methyl ferulic acid with high dosage (20 mg/kg), moderate dosage (10 mg/kg) and low dosage (5 mg/kg) groups. The general condition and organ index of each group were investigated. Histopathological analysis was performed to determine the degree of hepatic injury. Biochemical analyses of functional liver enzymes, lipid peroxidation enzymes and lipid content in each group. The levels of inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA). The mechanisms were investigated by detecting levels of NADPH Oxidase 4 (NOX4),p22phox, cytochrome P4502E1 (CYP2E1),Bax,B-cell lymphoma 2 (Bcl-2),cleaved-caspase 3 and 9 and phosphorylated extracellular regulated protein kinases(ERK),phosphorylated c-Jun N-terminal kinase (JNK), and phosphorylated p38 mitogen-activated protein kinase (MAPK) using real-time polymerase chain reaction (PCR) and Western blotting.. MFA treatment significantly decreased serum enzymatic activities of alanine aminotransferase (ALT) and aspartate aminotransaminase (AST). MFA markedly increased levels of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GSH-Px) and total antioxidative capacity (T-AOC), and reduced the concentration of malondialdehyde (MDA) and reactive oxygen species (ROS). Histopathological examination of livers showed that MFA reduced cytoplasmic vacuolisation necrosis and inflammatory cell infiltration in alcohol-treated mice. MFA treatment remarkably reduced the levels of trigyceride (TG), total cholesterol (TC) and low-density lipoprotein (LDL), decreasing the levels of high-density lipoprotein (HDL), alcohol dehydrogenase(ADL) and aldehyde dehydrogenase (ALDH). MFA treatment remarkably inhibited the expression of inflammatory factors tumour necrosis factor (TNF)-α, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-1β and IL-6. MFA attenuated both mRNA and protein expression of NOX4,p22phox,CYP2E1,Bax/Bcl-2. In addition, MFA inhibited the activation of caspase 3 and 9 and downregulated the levels of p-JNK,p-p38 MAPK and p-ERK in liver.. MFA has a protective effect on alcohol-induced liver injury, which may be related to its antioxidant,anti-inflammatory,lipid-eliminating properties and its ability to regulate the NOX4/ROS-MAPK signalling pathway.

Topics: Animals; Antioxidants; Caffeic Acids; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Ethanol; Liver Diseases, Alcoholic; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; NADPH Oxidase 4; NADPH Oxidases; Oxidative Stress; Reactive Oxygen Species; Treatment Outcome