Complement activation targeted inhibitor C2-FH ameliorates acetaminophen-induced liver injury in mice

BACKGROUND Complement activation is recognized as an important factor in the progression of liver damage caused by acetaminophen(APAP).However,the role of the complement inhibitor C2-FH in APAP-induced liver injury remains unclear.AIM To explore C2-FH in protecting against APAP-induced liver injury by inhibiting complement activation.METHODS A model of APAP-induced liver injury was used to study the protective effect of C2-FH on liver injury.C2-FH was administered through intraperitoneal injection 30 minutes after APAP treatment.We detected the effects of C2-FH on liver function,inflammatory response and complement activation.Additionally,RNA-sequencing(RNA-Seq)analysis was conducted to understand the mechanism through which C2-FH provides protection against APAP-induced liver injury.RESULTS C2-FH inhibited the increase in serum alanine aminotransferase activity,aspartate aminotransferase activity and lactate dehydrogenase,and reduced liver tissue necrosis caused by APAP.Moreover,it attenuated the inflammatory response and inhibited complement activation in APAP-induced liver injury.RNA-Seq analysis provided additional explanations for the protective role of C2-FH against APAP-induced liver injury.CONCLUSION C2-FH attenuates APAP-induced liver injury by inhibiting complement activation.

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.

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.

microRNA在对乙酰氨基酚所致肝损伤中抗损伤作用研究进展

药物引起的急性肝损伤(drug-induced liver injury,DILI)是导致肝衰竭的重要原因,其中以对乙酰氨基酚(acetaminophen,APAP)最常见。microRNA为一类非编码小RNA,在肝脏中具有重要的生物学功能,其对APAP所致肝损伤过程中代谢损伤、炎症发展以及肝再生等病理过程具有显著调控作用,对APAP所致肝损伤(acetaminophen-induced liver injury,AILI)发生发展产生重要影响。APAP所致的肝损伤能引起不同种类microRNA含量的变化,其中多种microRNA表达含量的变化能抑制炎症的发展,减轻肝损伤程度,对肝组织起保护作用。这属于机体应对损伤刺激时所表现的自我保护性机制。本文对在AILI中具有抗损伤作用的microRNA相关研究进行综述,并总结microRNA作用靶点与调控机制。