Functionalized selenium nanoparticles ameliorated acetaminophen-induced hepatotoxicity through synergistically triggering PKCδ/Nrf2 signaling pathway and inhibiting CYP 2E1

Selenium nanoparticles(SeNPs)have been demonstrated potential for use in diseases associated with oxidative stress.Functionalized SeNPs with lower toxicity and higher biocompatibility could bring better therapeutic activity and clinical application value.Herein,this work was conducted to investigate the protective effect of Pleurotus tuber-regium polysaccharide-protein complex funtionnalized SeNPs(PTR-SeNPs)against acetaminophen(APAP)-induced oxidative injure in HepG2 cells and C57BL/6J mouse liver.Further elucidation of the underlying molecular mechanism,in particular their modulation of Nrf2 signaling pathway was also performed.The results showed that PTR-SeNPs could significantly ameliorate APAP-induced oxidative injury as evidenced by a range of biochemical analysis,histopathological examination and immunoblotting study.PTR-SeNPs could hosphorylate and activate PKCδ,depress Keap1,and increase nuclear accumulation of Nrf2,resulting in upregulation of GCLC,GCLM,HO-1 and NQO-1 expression.Besides,PTR-SeNPs suppressed the biotransformation of APAP to generate intracellular ROS through CYP 2E1 inhibition,restoring the mitochondrial morphology.Furthermore,the protective effect of PTR-SeNPs against APAP induced hepatotoxicity was weakened as Nrf2 was depleted in vivo,indicating the pivotal role of Nrf2 signaling pathway in PTR-SeNPs mediated hepatoprotective efficacy.Being a potential hepatic protectant,PTR-SeNPs could serve as a new source of selenium supplement for health-promoting and biomedical applications.

A dual role of inflammation in acetaminophen-induced liver injury

In many affluent nations,acetaminophen(APAP)overdose is the leading cause of drug-induced acute liver failure.The process of APAP-induced liver injury(AILI)is intimately tied to inflammation,including hepatocyte necrosis-caused initiation of inflammation,inflammation amplification that exacerbates liver injury,and the resolution of inflammation that triggers liver regeneration and repair.Excessive APAP metabolism in the liver eventually leads to hepatocyte necrosis and inflammation.Innate immune cells,such as neutrophils,eosinophils,monocytes,and gammadelta T cells,are recruited into the injured liver and release various cytokines.These immune cells and cytokines have been found to serve two purposes in AILI.In this review,we highlighted the dual role of inflammation,including inflammatory cytokines and inflammatory immune cells in AILI,and discussed possible explanations for contradictory findings.

Molecular pathogenesis of acetaminophen-induced liver injury and its treatment options

Acetaminophen,also known as N-acetyl-p-aminophenol(APAP),is commonly used as an antipyretic and analgesic agent.APAP overdose can induce hepatic toxicity,known as acetaminophen-induced liver injury(AILI).However,therapeutic doses of APAP can also induce AILI in patients with excessive alcohol intake or who are fasting.Hence,there is a need to understand the potential pathological mechanisms underlying AILI.In this review,we summarize three main mechanisms involved in the pathogenesis of AILI:hepatocyte necrosis,sterile inflammation,and hepatocyte regeneration.The relevant factors are elucidated and discussed.For instance,N-acetyl-p-benzoquinone imine(NAPQI)protein adducts trigger mitochondrial oxidative/nitrosative stress during hepatocyte necrosis,danger-associated molecular patterns(DAMPs)are released to elicit sterile inflammation,and certain growth factors contribute to liver regeneration.Finally,we describe the current potential treatment options for AILI patients and promising novel strategies available to researchers and pharmacists.This review provides a clearer understanding of AILI-related mechanisms to guide drug screening and selection for the clinical treatment of AILI patients in the future.

Acetaminophen-Induced Acute Liver Failure Cured by Integrative Therapy of Chinese and Western Medicine—A Case Report

Introduction Acetaminophen （APP） is one of the most common antipyretic analgesics and is generally considered as a safe drug. However, acute or accumulative overdose of it can cause liver damage, even liver failure. Here we reported a case of an 11-year-old patient with acute liver failure （ALF） induced by taking 0.25 g APP orally, who was successfully treated by integrative Chinese and Western medicine.

Protective Effect of Fresh/Dry Dandelion Extracts on APAP-Overdose-Induced Acute Liver Injury

Objecitvie:To compare the liver protective activity of fresh/dried dandelion extracts against acetaminophen(APAP)-induced hepatotoxicity.Methods:Totally 90 Kunming mice were randomly divided into10 groups according to body weight(9 mice for each group).The mice in the normal control and model(vehicle control)groups were administered sodium carboxymethyl cellulose(CMC-Na,0.5%)only.Administration groups were pretreated with high and low-dose dry dandelion extract(1,000 or 500 g fresh herb dried and then decocted into 120 mL solution,DDE-H and DDE-L);low-,medium-and high-dose dandelion juice(250,500,1,000 g/120 mL,DJ-L,DJ-M,and DJ-H);fresh dandelions evaporation juice water(120 mL,DEJW);dry dandelion extract dissolved by pure water(1 kg/120 mL,DDED-PW);dry dandelion extract dissolved by DEJW(120 g/120 mL,DDED-DEJW)by oral gavage for 7 days at the dosage of 0.5 mL solution/10 g body weight;after that,except normal control group,all other groups were intraperitonealy injected with 350 mg/kg APAP to induce liver injury.Twenty hours after APAP administration,serum and liver tissue were collected and serum alanine aminotransferase(AST),aspartate transaminase(ALT),alkaline phosphatase(AKP),malondialdehyde(MDA),glutathione(GSH),superoxide dismutase(SOD)activities were quantified by biochemical kits;tumor necrosis factor(TNF-α),interleukin(IL)-2,and IL-1β contents in liver tissue were determined by enzyme linked immunosorbent assay kits.Histopathological changes in liver tissues were observed by hematoxylin and eosin staining;TUNEL Assay and Hoechst 33258 staining were applied for cell apoptosis evaluation.The expressions of heme oxygenase-1(HO-1),nuclear factor erythroid-2-related factor 2(Nrf-2),caspase-9,B-cell leukemia/lymphoma 2(Bcl-2),Bax and p-JNK were determined by Western blot analysis.Results:Pretreatment with fresh dandelion juice(FDJ,including DJ-L,DJ-M,DJ-H,DEJW and DDED-DEJW)significantly decreased the levels of serum ALT,AST,AKP,TNF-α and IL-1β compared with vehicle control group(P<0.05 or P<0.01).Additionally,compared with the vehicle control group,FDJ decreased the levels of hepatic MDA and restored GSH levels and SOD activity in livers(P<0.05 or P<0.01).FDJ inhibited the overexpression of pro-inflammatory factors including cyclooxygenase-2 and inducible nitric oxide synthase in the liver tissues(P<0.05 or P<0.01).Furthermore,Western blot analysis revealed that FDJ pretreatment inhibited activation of apoptotic signaling pathways via decreasing of Bax,and caspase-9 and JNK protein expression,and inhibited activation of JNK pathway(P<0.05 or P<0.01).Liver histopathological observation provided further evidence that FDJ pretreatment significantly inhibited APAP-induced hepatocyte necrosis,inflammatory cell infiltration and congestion.Conclusions:FDJ pretreatment protects against APAP-induced hepatic injury by activating the Nrf-2/HO-1 pathway and inhibition of the intrinsic apoptosis pathway,and the effect of fresh dandelion extracts was superior to dried dandelion extracts in APAP hepatotoxicity model mice.