Chrysanthemum Extract Alleviates Acetaminophen-induced Hepatotoxicity Via AMPK Pathway In Rats

Objective:Acetaminophen(APAP)is also known as bufferin and paracetamol.It is a commonly antipyretic analgesic in clinic.People use acetaminophen to address the pain of the disease while they also enduring the adverse effects in more than half a century.The most severe adverse effect is hepatotoxicity.If men use APAP with long-term or excessive or combination,APAP will lead to liver damage even death in severe cases.The drugs of therapeutic are limited,and it is urgent to develop new therapeutic drugs.?Bianliang Ziyu? is a chrysanthemum of Kaifeng.Our early studies have shown that Bianliang Ziyu alcohol extract(BZE)can alleviate the liver injury caused by APAP,but its mechanism is not very clear.This study aims to investigate the possible mechanisms of BZE on APAP-induced liver injury.Methods:Adult SD rats(220�20 g)were randomly divided into five groups: Control group,model group(APAP group),experimental group(three dosing groups).Experimental group were given BZE 110mg/kg/d,220mg/kg/d,440 mg/kg/d(0.5% sodium carboxymethyl cellulose solution preparation)for 10 days.APAP group and control group were given 0.5% sodium carboxymethyl cellulose solution by gavage at 1m L/d.Each group was free to drink and eat.After 24 hours of last administration,The experimental group and APAP group were given APAP(800mg/kg)by gavage to induce liver injury.All groups were given free drinking water and fasting.After 24 h liver samples were collected.The level of malondialdehyde-(MDA),reactive oxygen-(ROS),glutathione-(GSH)and superoxide dismutase-(SOD)in liver tissues were tested by the kits;The hepatic histopathological changes were observed by HE staining;And the effect of BZE on oxidative stress-related proteins,mitochondrial biosynthesis proteins,and apoptosis-related proteins were detected by western blot.Results:The results show that BZE could reverse the decrease of GSH and SOD levels and increase of MDA and ROS in APAP-induced liver.Further studies show that BZE improve the expression of mitochondrial biosynthesis-related proteins.Such as phosphorylated adenylate-activated protein kinase-(p-AMPK),phosphorylated glycogen synthase kinase 3?-(p-GSK-3?),nuclear factor erythroid 2-related factor 2-(Nrf2)and peroxisome proliferator-activated receptor gamma-(PPAR-?)and so on.Conclusion:The above results show that BZE may mediate the biosynthesis of GSK-3?-Nrf2 signaling pathway and mitochondria through AMPK pathway and alleviate the oxidative stress of hepatocytes,and thus improve the liver damage induced by APAP overdose in rats.