Acetaminophen overdose-induced acute liver injury can be alleviated by static magnetic field

Acetaminophen(APAP),the most frequently used mild analgesic and antipyretic drug worldwide,is implicated in causing 46%of all acute liver failures in the USA and between 40%and 70%in Europe.The predominant pharmacological intervention approved for mitigating such overdose is the antioxidant N-acetylcysteine(NAC);however,its efficacy is limited in cases of advanced liver injury or when administered at a late stage.In the current study,we discovered that treatment with a moderate intensity static magnetic field(SMF)notably reduced the mortality rate in mice subjected to high-dose APAP from 40%to 0%,proving effective at both the initial liver injury stage and the subsequent recovery stage.During the early phase of liver injury,SMF markedly reduced APAPinduced oxidative stress,free radicals,and liver damage,resulting in a reduction in multiple oxidative stress markers and an increase in the antioxidant glutathione(GSH).During the later stage of liver recovery,application of vertically downward SMF increased DNA synthesis and hepatocyte proliferation.Moreover,the combination of NAC and SMF significantly mitigated liver damage induced by high-dose APAP and increased liver recovery,even 24 h post overdose,when the effectiveness of NAC alone substantially declines.Overall,this study provides a noninvasive non-pharmaceutical tool that offers dual benefits in the injury and repair stages following APAP overdose.Of note,this tool can work as an alternative to or in combination with NAC to prevent or minimize liver damage induced by APAP,and potentially other toxic overdoses.

Milk fat globule epidermal growth factor 8 alleviates liver injury in severe acute pancreatitis by restoring autophagy flux and inhibiting ferroptosis in hepatocytes

BACKGROUND Liver injury is common in severe acute pancreatitis(SAP).Excessive autophagy often leads to an imbalance of homeostasis in hepatocytes,which induces lipid peroxidation and mitochondrial iron deposition and ultimately leads to ferroptosis.Our previous study found that milk fat globule epidermal growth factor 8(MFG-E8)alleviates acinar cell damage during SAP via binding toαvβ3/5 integrins.MFG-E8 also seems to mitigate pancreatic fibrosis via inhibiting chaperone-mediated autophagy.AIM To speculate whether MFG-E8 could also alleviate SAP induced liver injury by restoring the abnormal autophagy flux.METHODS SAP was induced in mice by 2 hly intraperitoneal injections of 4.0 g/kg L-arginine or 7 hly injections of 50μg/kg cerulein plus lipopolysaccharide.mfge8-knockout mice were used to study the effect of MFG-E8 deficiency on SAPinduced liver injury.Cilengitide,a specificαvβ3/5 integrin inhibitor,was used to investigate the possible mechanism of MFG-E8.RESULTS The results showed that MFG-E8 deficiency aggravated SAP-induced liver injury in mice,enhanced autophagy flux in hepatocyte,and worsened the degree of ferroptosis.Exogenous MFG-E8 reduced SAP-induced liver injury in a dose-dependent manner.Mechanistically,MFG-E8 mitigated excessive autophagy and inhibited ferroptosis in liver cells.Cilengitide abolished MFG-E8’s beneficial effects in SAP-induced liver injury.CONCLUSION MFG-E8 acts as an endogenous protective mediator in SAP-induced liver injury.MFG-E8 alleviates the excessive autophagy and inhibits ferroptosis in hepatocytes by binding to integrinαVβ3/5.

Wedelolactone attenuates sepsis-associated acute liver injury by regulating the macrophage M1/M2 polarization balance through the PI3K/AKT/NF-κB signalling pathway

Background:Liver injury caused by sepsis seriously impairs the normal physiology of the liver.Wedelactone(WED)has an obvious anti-inflammatory effect against liver damage caused by various factors.Nevertheless,further research is needed to determine if WED might mitigate acute liver damage linked to sepsis by influencing macrophage polarization.Methods:We first assessed the effect of WED on lipopolysaccharides-triggered liver injury by biochemistry assay and tissue staining.Inflammatory factors were assessed using the ELISA kits.The expression of Cluster of Differentiation 86(CD86)and Cluster of Differentiation 206(CD206)was measured by immunofluorescence assay.The protein levels of inducible nitric oxide sythase(iNOS),Arginase 1(Arg-1),phosphatidylinositol 3-kinase(PI3K),protein kinase B(AKT),PI3K phosphorylation(p-PI3K),AKT phosphorylation(p-AKT),inhibitor of kappa B kinase(IKK),inhibitor of kappa B(IκB),and nuclear factor kappa-B(NF-κB)p65 were quantified by western blot analysis.Results:WED decreased the level of alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP)and malondialdehyde,and increased the activity of superoxide dismutase(SOD)and glutathione peroxidase(GSH-PX).Moreover,WED exerted effective anti-inflammatory effects by decreasing the level of Tumor necrosis factor-α(TNF-α)and Interleukin 6(IL-6)and increasing the level of Interleukin 10(IL-10)in serum and cells.WED not only decreased CD86 and iNOS expression but also increased CD206 and Arg-1 expression.WED also downregulated the increased expression of PI3K,AKT,p-PI3K,p-AKT,IKK,and NF-κB p65 induced by lipopolysaccharides,while up-regulated the decreased expression of IκB.Besides,LY294002 with WED decreased the expression of protein PI3K,AKT,p-PI3K,p-AKT,IKK and NF-κB p65,and raised the expression of IκBα.Conclusion:Wedelolactone could attenuate sepsis-associated acute liver injury,and its mechanism may be associated with balancing pro-inflammatory and anti-inflammatory by the regulation of M1/M2 macrophage polarization via the PI3K/AKT/NF-κB signaling pathway.

Single-cell transcriptome analysis uncovers underlying mechanisms of acute liver injury induced by tripterygium glycosides tablet in mice

Tripterygium glycosides tablet(TGT),the classical commercial drug of Tripterygium wilfordii Hook.F.has been effectively used in the treatment of rheumatoid arthritis,nephrotic syndrome,leprosy,Behcet's syndrome,leprosy reaction and autoimmune hepatitis.However,due to its narrow and limited treatment window,TGT-induced organ toxicity(among which liver injury accounts for about 40%of clinical reports)has gained increasing attention.The present study aimed to clarify the cellular and molecular events underlying TGT-induced acute liver injury using single-cell RNA sequencing(scRNA-seq)technology.The TGT-induced acute liver injury mouse model was constructed through short-term TGT exposure and further verified by hematoxylin-eosin staining and liver function-related serum indicators,including alanine aminotransferase,aspartate aminotransferase,alkaline phosphatase and total bilirubin.Using the mouse model,we identified 15 specific subtypes of cells in the liver tissue,including endothelial cells,hepatocytes,cholangiocytes,and hepatic stellate cells.Further analysis indicated that TGT caused a significant inflammatory response in liver endothelial cells at different spatial locations;led to marked inflammatory response,apoptosis and fatty acid metabolism dysfunction in hepatocytes;activated hepatic stellate cells;brought about the activation,inflammation,and phagocytosis of liver capsular macrophages cells;resulted in immune dysfunction of liver lymphocytes;disturbed the intercellular crosstalk in liver microenvironment by regulating various signaling pathways.Thus,these findings elaborate the mechanism underlying TGT-induced acute liver injury,provide new insights into the safe and rational applications in the clinic,and complement the identification of new biomarkers and therapeutic targets for liver protection.

Scavenger receptor A-mediated nanoparticles target M1 macrophages for acute liver injury

Acute liver injury(ALI)has an elevated fatality rate due to untimely and ineffective treatment.Although,schisandrin B(SchB)has been extensively used to treat diverse liver diseases,its therapeutic efficacy on ALI was limited due to its high hydrophobicity.Palmitic acid-modified serum albumin(PSA)is not only an effective carrier for hydrophobic drugs,but also has a superb targeting effect via scavenger receptor-A(SR-A)on the M1 macrophages,which are potential therapeutic targets for ALI.Compared with the common macrophage-targeted delivery systems,PSA enables site-specific drug delivery to reduce off-target toxicity.Herein,we prepared SchB-PSA nanoparticles and further assessed their therapeutic effect on ALI.In vitro,compared with human serum albumin encapsulated SchB nanoparticles(SchB-HSA NPs),the SchB-PSA NPs exhibited more potent cytotoxicity on lipopolysaccharide(LPS)stimulated Raw264.7(LAR)cells,and LAR cells took up PSA NPs 8.79 times more than HSA NPs.As expected,the PSA NPs also accumulated more in the liver.Moreover,SchB-PSA NPs dramatically reduced the activation of NF-κB signaling,and significantly relieved inflammatory response and hepatic necrosis.Notably,the high dose of SchB-PSA NPs improved the survival rate in 72 h of ALI mice to 75%.Hence,SchB-PSA NPs are promising to treat ALI.

Optimization of Extraction Conditions of Pomegranate Peel Polyphenols and Its Protective Effect on Acute Alcoholic Liver Injury in Mice

[Objectives]This study was conducted to explore the optimization of ultrasonic-assisted organic solvent extraction of pomegranate peel polyphenols(PPPs),and to study the protective effect of PPPs on acute alcoholic liver injury in mice.[Methods]The optimal extraction conditions of PPPs were determined by single factor and orthogonal experiments,and an acute alcoholic liver injury model in mice was established.Bifendate was used as the positive control group to investigate the protective effect of low,medium and high doses of PPPs on acute alcoholic liver injury.[Results]The optimum extraction process parameters were followed as 60%ethanol concentration,solid-liquid ratio of 1:40(w/v),extraction temperature of 50℃,and extraction time of 1.5 h,and the yield was 1.42%.The results of animal experiments showed that PPPs could effectively reduce the degree of alcoholic liver injury in mice,reduce the levels of serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST),and reduce the inflammation and necrosis of liver tissue in mice.Meanwhile,the total polyphenols from pomegranate peel also significantly reduced the expression levels of malondialdehyde(MDA),tumor necrosis factor(TNF-α)and interleukin-6(IL-6)in mice,and increased the levels of superoxide dismutase(SOD)and reduced glutathione(GSH)in liver tissue of mice,indicating its antioxidant and anti-inflammatory effects,further illustrating its protective effect on alcoholic liver injury.[Conclusions]PPPs could reduce the expression levels of TNF-α,IL-6 and MDA in mice,and increase the expression levels of SOD and GSH to achieve the protective effect on acute alcoholic liver injury in mice.This study will provide new ideas for the development of new anti-alcoholic liver injury drug resources.

Severe acute respiratory syndrome coronavirus 2 may cause liver injury via Na^(+)/H^(+) exchanger

The liver has many significant functions,such as detoxification,the urea cycle,gluconeogenesis,and protein synthesis.Systemic diseases,hypoxia,infections,drugs,and toxins can easily affect the liver,which is extremely sensitive to injury.Systemic infection of severe acute respiratory syndrome coronavirus 2 can cause liver damage.The primary regulator of intracellular pH in the liver is the Na+/H+exchanger(NHE).Physiologically,NHE protects hepatocytes from apoptosis by making the intracellular pH alkaline.Severe acute respiratory syndrome coronavirus 2 increases local angiotensin II levels by binding to angiotensinconverting enzyme 2.In severe cases of coronavirus disease 2019,high angiotensin II levels may cause NHE overstimulation and lipid accumulation in the liver.NHE overstimulation can lead to hepatocyte death.NHE overstimulation may trigger a cytokine storm by increasing proinflammatory cytokines in the liver.Since the release of proinflammatory cytokines such as interleukin-6 increases with NHE activation,the virus may indirectly cause an increase in fibrinogen and D-dimer levels.NHE overstimulation may cause thrombotic events and systemic damage by increasing fibrinogen levels and cytokine release.Also,NHE overstimulation causes an increase in the urea cycle while inhibiting vitamin D synthesis and gluconeogenesis in the liver.Increasing NHE3 activity leads to Na+loading,which impairs the containment and fluidity of bile acid.NHE overstimulation can change the gut microbiota composition by disrupting the structure and fluidity of bile acid,thus triggering systemic damage.Unlike other tissues,tumor necrosis factor-alpha and angiotensin II decrease NHE3 activity in the intestine.Thus,increased luminal Na+leads to diarrhea and cytokine release.Severe acute respiratory syndrome coronavirus 2-induced local and systemic damage can be improved by preventing virus-induced NHE overstimulation in the liver.

MRI shows clodronate-liposomes attenuating liver injury in rats with severe acute pancreatitis

BACKGROUND: Studies have revealed that macrophages play an important role in the development of severe acute pancreatitis (SAP). Activated macrophages can lead to a systemic inflammatory response, induce lipid peroxidation, impair membrane structure, result in injury to the liver and the other extrahepatic organs, and eventually result in multiple organ dysfunction syndrome by promoting excessive secretion of cytokines. Liver injury can further aggravate the systemic inflammatory response and increase mortality by affecting the metabolism of toxins and the release of excessive inflammatory mediators. Clodronate is a synthetic bisphosphonate, which is often used for treating bone changes caused by osteoporosis and other factors. In the current study, we created liposomes containing superparamagnetic iron oxide particles (SPIOs) for macrophage labeling and magnetic resonance imaging, using a novel method that can bind the clodronate to induce apoptosis and deplete macrophages. METHODS: Superparamagnetic Fe(3)O(4) nanoparticles were prepared by chemical coprecipitation. SPIO-containing liposomes and SPIO-clodronate-containing liposomes were prepared by the thin film method. SAP models were prepared by injection of sodium taurocholate (2 ml/kg body weight) into the subcapsular space of the pancreas. Sprague-Dawley rats were randomly divided into a control group, a SAP plus SPIO-liposome group, and a SAP plus SPIO-clodronate-containing group. Two and six hours after SAP models were available, T2-weighted MRI scans (in the same plane) of the livers of rats in each group were performed. At the end of the scans, 2 ml of blood was taken from the superior mesenteric vein to measure the levels of serum amylase, ALT, AST, TNF-alpha, and IL-6. Pathological changes in the liver and pancreas were assessed. RESULTS: Transmission electron microscopy showed that the liposomes had a uniform size. No pathological changes in the pancreata of rats in the control group were noted. The pathological changes in the pancreata and livers of rats in the SAP plus SPIO-clodronate-containing liposome group were milder than those in the SAP plus SPIO-liposome group. The MRI signal intensity of the livers in the SAP plus SPIO-liposome and SAP plus SPIO-clodronate-containing groups was significantly lower than that in the control group. There were significant changes in the two experimental groups (P<0.01). In addition, the levels of serum amylase, ALT, AST, TNF-alpha, and IL-6 in rats in the SAP plus SPIO-liposome group were higher than those in the control group (P<0.01), while the corresponding levels in the SPIO-clodronate-containing liposome group were significantly lower than those in the SAP plus SPIO-liposome group (P<0.01). CONCLUSION: Clodronate-containing liposomes protect against liver injury in SAP rats, and SPIO can be used as a tracer for MRI examination following liver injury in SAP rats. (Hepatobiliary Pancreat Dis Int 2010; 9: 192-200)

Acute Toxicity of Jinchuan Formula Plum Wine Extract and Its Protective Effect on Mice with Liver Injury

[Objectives]To investigate the acute toxicity and hepatoprotective effect of Jinchuan formula plum wine extract on mice,determine its safety range,and evaluate its hepatoprotective effect.[Methods]The median lethal dose(LD_(50))was determined by acute toxicity test with the toxic reaction and mortality of mice as indexes.Sixty Kunming mice were randomly divided into 6 groups:normal control group,model group(ConA-induced liver injury model),Jinchuan formula plum wine high,medium and low dose groups(1.0,0.5,0.25 g/kg)and silybin group(0.1 g/kg).The levels of ALT,AST,LDH in serum and TG,VLDL in liver were measured.After HE staining,the pathological changes of liver tissue in mice were observed,and the liver protective effect of Jinchuan formula plum wine extract was analyzed and evaluated.[Results]LD_(50)was 11.18 g/kg,and the 95%confidence limit of LD_(50)was 10.31-12.05 g/kg.The high-dose group of Jinchuan formula plum wine extract could significantly reduce the serum ALT and AST activities of ConA-induced liver injury mice(P<0.05).[Conclusions]Jinchuan formula plum wine extract is relatively safe,and also has a protective effect on liver injury.

Hepatoprotective effects of baicalein against CCl 4-induced acute liver injury in mice

AIM:To investigate the hepatoprotective effect of baicalein against carbon tetrachloride(CCl 4)-induced liver damage in mice.METHODS:Mice were orally administered with baicalein after CCl 4 injection,and therapeutic baicalein was given twice a day for 4 d.The anti-inflammation effects of baicalein were assessed directly by hepatic histology and serum alanine aminotranferease and aspartate aminotransferase measurement.Proliferating cell nuclear antigen was used to evaluate the effect of baicalein in promoting hepatocyte proliferation.Serum interleukin(IL)-6,IL-1β and tumor necrosis factor-α(TNF-α) levels were measured by enzyme-linked immunosorbent assay and liver IL-6,TNF-α,transforming growth factor-α(TGF-α),hepatocyte growth factor(HGF) and epidermal growth factor(EGF) genes expression were determined by quantitative real-time polymerase chain reaction.RESULTS:CCl4-induced acute liver failure model offers a survival benefit in baicalein-treated mice.The data indicated that the mRNA levels of IL-6 and TNF-α significantly increased within 12 h after CCl 4 treatment in baicalein administration groups,but at 24,48 and 72 h,the expression of IL-6 and TNF-α was kept at lower levels compared with the control.The expression of TGF-α,HGF and EGF was enhanced dramatically in baicalein administration group at 12,24,48 and 72 h.Furthermore,we found that baicalein significantly elevated the serum level of TNF-α and IL-6 at the early phase,which indicated that baicalein could facilitate the initiating events in liver regeneration.CONCLUSION:Baicalein may be a therapeutic candidate for acute liver injury.Baicalein accelerates liver regeneration by regulating TNF-α and IL-6 mediated pathways.

Protective effect of recombinant human IL-1Ra on CCl_4-induced acute liver injury in mice

AIM: To evaluate the effects of positive regulation of recombinant human interleukin 1 receptor antagonist (rhIL-1Ra) on hepatic tissue recovery in acute liver injury in mice induced by carbon tetrachloride (CCl 4 ). METHODS: Acute liver damage was induced by injecting 8-wk-old mice with CCl 4 1 mL/kg (1:3 dilution in corn oil) intraperitoneally (ip). Survival after liver failure was assessed by injecting 8-wk-old mice with a lethal dose of CCl 4 2.6 mL/kg (1:1 dilution in corn oil) ip. Mice were subcutaneously injected with 1 mg/kg recombinant human IL-1Ra twice a day after CCl 4 treatment for 5 d. Serum alanine amino transferase (ALT) and aspartate aminotransferase (AST) levels were determined with a commercial assay kit. Serum IL-1β, IL-1Ra levels were measured by enzyme-linked immunosorbent assay kit. Quantitative real-time polymerase chain reaction was used to determine liver IL-1β, IL-1Ra and IL-6 expression during CCl 4-induced acute liver injury. Liver sections were stained with hematoxylin-eosin. A histology-injury grading system was used to evaluate the degree of necrosis after acute liver injury. Proliferating cell nuclear antigen (PCNA) staining was used to evaluate the role of rhIL-1Ra in promoting hepatocyte proliferation. RESULTS: Quantitative analysis showed a higher level of IL-6 mRNA expression and reduced serum AST and ALT levels in the livers of the rhIL-1Ra-treated group at the early phase of CCl 4-induced acute liver injury. Histological examination indicated a decrease in centrilobular necrotic areas in mice treated with rhIL-1Ra, and a novel role of rhIL-1Ra in promoting hepatocyte proliferation was also supported by an increase of PCNA staining. All these results, accompanied by a strong survival benefit in rhIL-1Ra-treated vs PBS-treated groups, demonstrated that rhIL-1Ra administration ameliorated the histological damage and accelerated the regeneration and recovery process of the liver. CONCLUSION: rhIL-1Ra could be further developed as a novel therapeutic agent for the treatment of acute liver injury because of its ability to reduce hepatocellular damage and facilitate liver regeneration.

Liver injury associated with acute pancreatitis:The current status of clinical evaluation and involved mechanisms

Acute pancreatitis(AP)is a very common acute disease,and the mortality rate of severe AP(SAP)is between 15%and 35%.The main causes of death are multiple organ dysfunction syndrome and infections.The mortality rate of patients with SAP related to liver failure is as high as 83%,and approximately 5%of the SAP patients have fulminant liver failure.Liver function is closely related to the progression and prognosis of AP.In this review,we aim to elaborate on the clinical manifestations and mechanism of liver injury in patients with AP.

Protective effect of fufanghuangqiduogan against acute liver injury in mice

AIM: To study the effects and possible mechanisms of fufanghuangqiduogan (FFHQ) in mice with acute liver injury (ALI). METHODS: ALI was successfully induced by injecting carbon tetrachloride (CCl4) intra peritoneally and by tail vein injection of Bacillus Calmette Guerin (BCG) and lipopolysaccharide (LPS) in mice, respectively. Each of the two model groups was divided into normal group, model group, FFHQ (60, 120 and 240 mg/kg) treatment groups, and bifendate treatment group. At the end of the experiment, levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), content of malondialdehyde (MDA), activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) in liver homogenate were measured by biochemical methods. The activities of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) were determined by radio-immunoassay. Hepatic tissue sections were stained with hematoxylin and eosin and examined under a light microscope. RESULTS: In the two models of ALI, FFHQ (60, 120, 240 mg/kg) was found to significantly decrease the serum transaminase (ALT, AST) activities. Meanwhile, FFHQ decreased MDA contents and upregulated the lower SOD and GSH-px levels in liver homogenate. Furthermore, in immunologic liver injury model, FFHQ decreased levels of TNF-α and IL-1 in serum. Histologic examination showed that FFHQ could attenuate the area and extent of necrosis, reduce the immigration of inflammatory cells. CONCLUSION: FFHQ had protective effect on liver injury induced by either CCl4 or BCG+LPS in mice, and its mechanisms were related to free radical scavenging, increasing SOD and GSH-px activities and inhibiting the production of proinflammatory mediators.

Macrophage inflammatory protein-2 as mediator of inflammation in acute liver injury

Macrophage inflammatory protein(MIP)-2 is one of the CXC chemokines and is also known as chemokine CXC ligand(CXCL2). MIP-2 affects neutrophil recruitment and activation through the p38 mitogen-activatedprotein-kinase-dependent signaling pathway, by binding to its specific receptors, CXCR1 and CXCR2. MIP-2 is produced by a variety of cell types, such as macrophages, monocytes, epithelial cells, and hepatocytes, in response to infection or injury. In liver injury, activated Kupffer cells are known as the major source of MIP-2. MIP-2-recruited and activated neutrophils can accelerate liver inflammation by releasing various inflammatory mediators. Here, we give a brief introduction to the basic molecular and cellular sources of MIP-2, and focus on its physiological and pathological functions in acute liver injury induced by concanavalin A, lipopolysaccharides, irradiation, ischemia/reperfusion, alcohol, and hypoxia, and hepatectomy-induced liver regeneration and tumor colorectal metastasis. Further understanding of the regulatory mechanisms of MIP-2 secretion and activation may be helpful to develop MIP-2-targeted therapeutic strategies to prevent liver inflammation.

Role of the^(13)C-methacetin breath test in the assessment of acute liver injury in a rat model

AIM: To evaluate the role of the 13C-methacetin breath test(13C-MBT) in the assessment of acute liver injury in a rat model.METHODS: Acute liver injury in rats was induced by a single intraperitoneal injection of D-galactosamine(D-GalN). Forty-eight male Sprague-Dawley rats were randomly assigned to a control group(n = 8) and five model groups(each n = 8), and acute liver injury was assessed at different time points(6, 12, 24, 48 and 72 h) after D-GalN injection. The 13C-MBT, biochemical tests, 15-min retention rate of indocyanine green(ICGR15), and liver biopsy were performed and compared between the control and model groups. Correlations between parameters of the 13C-MBT(Tmax, MVmax, CUM120 and DOBmax), biochemical tests, ICGR15 and liver necrosis score were also analyzed using Spearman'scorrelation analysis.RESULTS: Tmax, MVmax, CUM120 and DOBmax, as well as most of the traditional methods, correlated with the liver necrosis score(r = 0.493, P < 0.05; r =-0.731, P < 0.01; r =-0.618, P < 0.01; r =-0.592, P < 0.01, respectively). MVmax, CUM120 and DOBmax rapidly decreased and were lower than those in the controls as early as 6 h after D-GalN injection(3.84 ± 0.84 vs 5.06 ± 0.78, P < 0.01; 3.35 ± 0.72 vs 4.21 ± 1.44, P < 0.05; 52.3 ± 20.58 vs 75.1 ± 9.57, P < 0.05, respectively) and reached the lowest point 24 h after D-GalN injection. MVmax, CUM120 and DOBmax returned to normal levels 72 h after D-GalN injection and preceded most of the traditional methods, including liver biopsy.CONCLUSION: The 13C-MBT is a sensitive tool for the timely detection of acute liver injury and early prediction of recovery in a rat model. Further clinical studies are warranted to validate its role in patients with acute liver injury.

Protective Effect of Procyanidin B2 on Acute Liver Injury Induced by Aflatoxin B1 in Rats

Objective This study aimed to explore the protective effect of procyanidin B2(PCB2)on acute liver injury induced by aflatoxin B1(AFB1)in rats.Methods Forty Sprague Dawley rats were randomly divided into control,AFB1,AFB1+PCB2,and PCB2 groups.The latter two groups were administrated PCB2 intragastrically(30 mg/kg body weight)for 7 d,whereas the control and AFB1 groups were given the same dose of double distilled water intragastrically.On the sixth day of treatment,the AFB1 and AFB1+PCB2 groups were intraperitoneally injected with AFB1(2 mg/kg).The control and PCB2 groups were intraperitoneally administered the same dose of dimethyl sulfoxide(DMSO).On the eighth day,all rats were euthanized:serum and liver tissue were isolated for further examination.Hepatic histological features were assessed by hematoxylin and eosin-stained sections.Weight,organ coefficient(liver,spleen,and kidney),liver function(serum alanine aminotransferase,aspartate aminotransferase,alkaline phosphatase,total bilirubin,and direct bilirubin),oxidative index(catalase,glutathione,superoxide dismutase,malondialdehyde,and 8-hydroxy-2′-deoxyguanosine),inflammation factor[hepatic interleukin-6(IL-6)m RNA expression and serum IL-6],and bcl-2/bax ratio were measured.Results AFB1 significantly caused hepatic histopathological damage,abnormal liver function,oxidative stress,inflammation,and bcl-2/bax ratio reduction compared with DMSO-treated controls.Our results indicate that PCB2 treatment can partially reverse the adverse liver conditions induced by AFB1.Conclusion Our findings indicate that PCB2 exhibits a protective effect on acute liver injury induced by AFB1.

Hepatitis E virus in patients with acute severe liver injury

AIM: To examine the incidence of hepatitis E(HepE) in individuals with acute liver injury severe enough to warrant treatment at a transplant unit.METHODS: Hepatitis E virus(HEV) is an emerging pathogen in developed countries causing severe illness, particularly in immunocompromised patients or those with underlying chronic liver disease. HepE infection isoften under diagnosed, as clinicians can be reluctant to test patients who have not travelled to regions traditionally considered hyperendemic for HepE. There are few data regarding the significance of HEV in patients with very severe acute liver injury in developed countries. Eighty patients with acute severe liver injury attending the Scottish Liver Transplant unit were tested for HEV and anti-HEV IgG and IgM. Severe acute liver injury was defined as a sudden deterioration in liver function confirmed by abnormal liver function tests and coagulopathy or presence of hepatic encephalopathy. Eighty percent of these patients were diagnosed with paracetomol overdose. No patients had a history of chronic or decompensated chronic liver disease at time of sampling. IgG positive samples were quantified against the World Health Organization anti-HEV IgG standard. Samples were screened for HEV viral RNA by quantitative reverse transcription polymerase chain reaction.RESULTS: Four cases of hepatitis E were identified. Three of the four cases were only diagnosed on retrospective testing and were initially erroneously ascribed to drug-induced liver injury and decompensated chronic liver disease, with the cause of the decompensation uncertain. One case was caused by HEV genotype 1 in a traveller returning from Asia, the other three were autochthonous and diagnosed on retrospective testing. In two of these cases(where RNA was detected) HEV was found to be genotype 3, the most prevalent genotype in developed countries. Three patients survived, two of whom had been misdiagnosed as having drug induced liver injury. The fourth patient died from sepsis and liver failure precipitated as a result of hepatitis E infection and previously undiagnosed cirrhosis. Histopathology data to date is limited to mainly that seen for endemic HepE. All patients, with the exception of patient 1, demonstrated characteristics of HepE infection, as seen in previously described locally acquired cases.CONCLUSION: In patients with acute severe liver injury, HEV testing should be part of the initial diagnostic investigation algorithm irrespective of suspected initial diagnosis, age or travel history.

Protective effect of glutamine in critical patients with acute liver injury

BACKGROUND：Glutamine （Gin） supplementation is known to decrease oxidative stress and inflammatory response, enhance resistance to infectious pathogens, shorten hospital stay, and decrease medical costs of patients. This study was undertaken to evaluate the relationship between the effect of early parenteral glutamine （Gin） supplement on acute liver injury （ALl） and heat shock protein 70 （HSP-70） expression in critical patients. METHODS：Forty-four patients who had been admitted to the emergency intensive care unit （EICU） of Nanjing First Hospital Affiliated to Nanjing Medical University were randomly divided into a control group （n=22） and a Gin group （n=22）. The patients of the two groups received enteral and parenteral nutrition. In addition, parenteral Gin 0.4 g/kg per day was given for 7 days in the Gin group. Serum HSP-70 and Gin were measured at admission and at 7 days after admission. Serum alanine aminotransferase （ALT）, aspartate aminotransferase （AST）, and total bilirubin （TBiL）, serum levels of HSP-70 and Gin, mechanical ventilation （MV） time, ICU stay, peripheral blood of TNF-α, IL- 6, CD3, CD4 and CD4/CD8 levels were also measured in the two groups. RESULTS： In the Gin group, the levels of serum HSP-70 and Gin were significantly higher after Gin treatment than those before the treatment （P〈0.01）. HSP-70 level was positively correlated with the Gin level in the Gin group after administration of parenteral Gin （P〈0.01）. The levels of serum ALT, AST, TBiL and TNF-a, IL-6 were lower in the Gin group than in the non-Gin group （P〈0.01）. MV time and ICU stay were significantly different between the two groups （P〈0.05）. The levels of CD3, CD4 and CD4/ CD8 were significantly higher in the Gin group than in the control group after treatment （P〈0.05）. CONCLUSION：Parenteral Gin significantly increases the level of serum HSP70 in critically ill patients. The enhanced expression of HSP70 is correlated with improved outcomes of Gin-treated patients with acute liver injury.

Liver infiltration of multiple immune cells during the process of acute liver injury and repair

BACKGROUND Immune cells,including neutrophils,natural killer(NK)cells,T cells,NKT cells and macrophages,participate in the progression of acute liver injury and hepatic recovery.To date,there has been no systematic study on the quantitative changes in these different immune cells from initial injury to subsequent recovery.AIM To investigate the infiltration changes of various immune cells in acute liver injury models over time,and to study the relationship between the changes in leukocyte cellderived chemotaxin 2(LECT2)and the infiltration of several immune cells.METHODS Carbon tetrachloride-and concanavalin A-induced acute liver injury models were employed to mimic toxin-induced and autoimmune-mediated liver injury respectively.The quantitative changes in various immune cells were monitored at different time points.Serum samples were collected,and liver tissues were harvested.Ly6G,CD161,CD4,CD8 and F4/80 staining were used to indicate neutrophils,NK/NKT cells,CD4^(+)T cells,CD8^(+)T cells and macrophages,respectively.Lect2-KO mice were used to detect the function of LECT2.RESULTS During the injury and repair process,different types of immune cells began to increase,reached their peaks and fell into decline at different time points.Furthermore,when the serum alanine transaminase(ALT)and aspartate transaminase(AST)indices reverted to normal levels 7 d after the injury,the infiltration of immune cells still existed even 14 d after the injury,showing an obvious lag effect.We found that the expression of LECT2 was upregulated in acute liver injury mouse models,and the liver injuries of Lect2-KO mice were less severe than those of wild-type mice.Compared with wild-type mice,Lect2-KO mice had different immune cell infiltration.CONCLUSION The recovery time of immune cells was far behind that of serum ALT and AST during the process of liver repair.LECT2 could regulate monocyte/macrophage chemotaxis and might be used as a therapeutic target for acute liver injury.

Effects of a combination of Japanese Raisin Tree Seed and Flower of Lobed Kudzuvine against acute alcohol-induced liver injury in mice

Objective:The Flower of Lobed Kudzuvine[Pueraria lobata(Willd.)Ohwi;Gehua in Chinese;GH]and Japanese Raisin Tree Seed(Hovenia dulcis Thunnb.;Zhijuzi in Chinese;ZJZ)are herbs that have been used in China for the treatment of alcohol intoxication and liver diseases.We aimed to evaluate the hepatoprotective potential of a combination of these in mice with acute alcohol-induced liver injury,and to elucidate the mechanisms involved.Methods:Male ICR mice were randomly allocated to six groups:a control group,an alcohol-administered group,and groups that were administered alcohol and one of silibinin,the GH,the ZJZ or a GH-ZJZ combination(at a ratio of 2:1).Animals were orally administered 56%alcohol(Er Guo-tou white spirit,0.12 mL/10 g/d)for 10 days and at the end of this period,hepatic biochemical indicators,antioxidant parameters,alcohol metabolic enzymes,and histopathologic changes were evaluated.Moreover,the expression of the signaling molecules KEAP1,NRF2,and AQP9 were measured by qRT-PCR and western blotting.Results:Compared with the model group,GH-ZJZ(2:1)had lower serum ALT(12.15±0.39,P紏.003),AST(104.07±1.03,P紏.001),and ALP(148.09±2.55,P紏.010)activities,and lower TC(1.97±0.05,P紏.001)and TG(1.54±0.07,P?.002)concentrations.GH-ZJZ(2:1)also significantly increased the hepatic activities of SOD and GSH(4.24±0.25 and 1.57±0.06,respectively;both P<.01),reduced the ROS and MDA concentrations(97.50±3.00 and 2.39±0.19,respectively;both P<.01),and upregulated Nrf2 expression(P<.01).GH-ZJZ(2:1)significantly reduced the expression of KEAP1 and AQP9 in the liver,compared with alcohol-administered mice(P<.01).Importantly,the GH-ZJZ combination caused a more marked improvement in acute liver injury than GH or ZJZ alone.Conclusion:We have demonstrated protective effects of GH-ZJZ(2:1)against acute alcohol-induced hepatic injury,and shown that these effects may be associated with improvements in lipid and alcohol metabolism,antioxidant capacity,and lipid peroxidation.