The Hepatoprotective Effects Of Ginsenosides From The Leaves And Berry Of Panax Quinquefolium On Acetaminophen-Induced Hepatotoxicity In Mice And Its Molecular Mechanism

Panax quinquefolium is one of the most well-known perennial herbal plants of the genus Panax(family Araliaceae).Its roots and rhizomes have served as drugs,dietary supplements,and foods for 300 years.Panax quinquefolium are famous for its outstanding pharmacological activities.It mainly contains active ingredients such as saponins,sugars,polyacetylenes,fatty acids,amino acids,sterols,flavonoids,inorganic elements and volatile oils,ginsenosides are thought to be the main active ingredients in that.Recent studies showed that PQS and AGB have various pharmacological activities.PQS has potential pharmacological activities in improving immunity,anti-myocardial ischemia,anti-tumor,hypoglycemic,hypolipidemic,and cognition ability.Similar to PQS,AGB has potential effects in anti-tumor,myocardial protection,hypoglycemic,anti-oxidation and enhancing brain memory ability.Researchers have been focusing on the main research on the root of P.quinquefolium all the time,but there are few researches on its stems,leaves and berry.In order to sufficiently utilize the aboveground resources of P.quinquefolium and enhance the economic value of American ginseng industry,American ginseng stems,leaves and berry biological activity carried out in-depth study.Drug-induced liver injury has overtaken viral hepatitis to become the leading cause of ALF in the United States and is more common than all other causes combined Acetaminophen toxicity is the most common cause of severe intrinsic DILI in the United States,representing approximately 50% of all ALF cases.Therefore,the study of APAP-induced liver injury is more significant.The main purpose of this paper was to investigate the liver protection activity of saponins(ginsenosides)from the leaves of Panax quinquefolium(PQS)against APAP-induced hepatotoxicity.Male ICR mice were randomly divided into four groups: Normal group,APAP group,APAP+PQS(150mg/kg,300mg/kg)groups,each group has 8 mice.Mice were pretreated with PQS(150 and 300 mg/kg)by oral gavage for 7 days before being treated with 250 mg/kg APAP(65℃ dissolved).Our results showed that pretreatment with PQS significantly decreased the serum alanine aminotransferase(GPT),aspartate transaminase(GOT),tumor necrosis factor(TNF-α),and interleukin-1β(IL-1β)levels in a dose-dependent manner as compared to the APAP administration.Meanwhile,compared with that in the APAPgroup,PQS decreased hepatic malondialdehyde(MDA)contents and4-hydroxynonenal(4-HNE)expression and restored reduced glutathione(GSH)content and superoxide dismutase(SOD)activity in livers of mice.PQS inhibited the overexpression of pro-inflammatory factors cyclooxygenase-2(COX-2)and inducible nitric oxide synthase(iNOS)in the liver tissues.Furthermore,Western blotting analysis revealed that PQS pretreatment inhibited the activation of apoptotic signaling pathways via increase of Bcl-2 and decrease of Bax and caspase-3 protein expression levels.Liver histopathological observation provided further evidence that PQS pretreatment significantly inhibited APAP-induced hepatocyte necrosis,inflammatory cell infiltration,and congestion.Biological indicators of nitrative stress such as 3-nitrotyrosine(3-NT)were inhibited after PQS pretreatment,compared to the APAP group.The present study clearly demonstrates that PQS exerts a protective effect against APAP-induced hepatic injury because of its antioxidant,anti-apoptotic,and anti-inflammatory activities.The findings from the present investigation show that PQS might be a promising candidate treatment agent against drug-induced ALI.Similar to the leaves of P.Quinquefolium,American ginseng berry(AGB)is another important part with therapeutic potential.Based on our previous observation,this investigation was to assess the hepatic protective effects for novel mechanisms of AGB using Acetaminophen(APAP)-induced liver injury models.The Similar to the PQS experiment design.Our study results demonstrated AGB pretreatment ameliorated APAP-induced hepatic injury as evidenced by decreases in plasma alanine aminotransferase(GPT),aspartate transaminase(GOT),tumor necrosis factor α(TNF-α),and interleukin-1β(IL-1β)compared to the APAP group.Western blotting analysis showed that AGB pretreatment decreased the expressions of TNF-α and nuclear transcription factor-κB(NF-κB p65)in liver cells.Meanwhile,the hepatocyte expression levels of cytochrome c,Bax and Caspases were elevated by AGB treatment,while the Bcl-2 protein expression was reduced in comparison with that in APAP only group.Furthermore,AGB treatment showed anti-oxidant effectswith increase in hepatic Superoxide dismutase(SOD)levels,and decreases in malondialdehyde(MDA)contents,4-hydroxynonenal(4-HNE),cytochrome P450E1(CYP2E1)expression,and glutathione(GSH)depletion.Histopathological data demonstrated that AGB pretreatment inhibited APAP-induced hepatocyte toxicity.Collectively,the present study demonstrated that AGB pretreatment protected livercells against APAP-induced hepatotoxicity through inhibiting oxidant activities,inflammation responses,and TNF-α-mediated caspase-3/-8/-9 signaling pathways.Taken together,in the above two different types of acute liver injury experiments in mice,PQS and AGB effectively ameliorate acute liver injury APAP-induced by improving antioxidant enzymies activities and inhibiting lipid peroxidation,inflammation,apoptosis and necrosis.The results showed PQS and AGB have a high quality of biological activity.Meanwhile,PQS and AGB are inexpensive and convenient,so they might be a promising candidate treatment agent against drug-induced acute liver injury.