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.

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.

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.

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.

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.

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 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.

Effects of Salmonella infection on hepatic damage following acute liver injury in rats

BACKGROUND： Acute liver injury is a common clinical disorder associated with intestinal barrier injury and disturbance of intestinal microbiota. Probiotic supplementation has been reported to reduce liver injury; however, it is unclear whether enteropathogen infection exacerbates liver injury. The purpose of this study was to address this unanswered question using a rat model. METHODS： Oral supplementation with Salmonella enterica serovar enteritidis（S. enteritidis） was given to rats for 7 days. Different degrees of acute liver injury were then induced by intraperitoneal injection of D-galactosamine. The presence and extent of liver injury was assayed by measuring the concentrations of serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin. Histology was used to observe liver tissue damage. Additionally, we measured the changes in plasma endotoxin, serum cytokines and bacterial translocation to clarify the mechanisms underlying intestinal microbiota associated liver injury.RESULTS： The levels of liver damage and endotoxin were significantly increased in the Salmonella infected rats with severe liver injury compared with the no infection rats with severe liver injury（P〈0.01）; The peyer＇s patch CD3＋ T cell counts were increased significantly when the Salmonella infection with severe injury group was compared with the normal group（P〈0.05）. S. enteritidis pretreatment enhanced intestinal barrier impairment and bacterial translocation.CONCLUSIONS： Oral S. enteritidis administration exacerbates acute liver injury, especially when injury was severe.Major factors of the exacerbation include inflammatory and oxidative stress injuries induced by the translocated bacteria and associated endotoxins, as well as over-activation of the immune system in the intestine and liver.

Protection Effect of Qiwei Jingganling on Carbon Tetrachloride-induced Acute Liver Injury in Mice

[Objectives] The aim was to study the protection effect of Qiwei Jingganling on carbon tetrachloride-induced acute liver injury in mice and its mechanism of action. [Methods]Total 60 mice were randomly and evenly divided into 6 groups,normal group,model group,silymarin group( 150 mg/kg),high-dose Qiwei Jingganling group( 8 g/kg,crude drug),middle-dose Qiwei Jingganling group( 4 g/kg,crude drug) and low-dose Qiwei Jingganling group( 2 g/kg,crude drug). The mice were administered orally once a day according to the amount of10 m L/kg,and 10-day continuous administration was carried out. After 2 h of the last administration,0. 12% CCl4 peanut oil solution( 10 m L/kg) was injected intraperitoneally to all the mice except those in the normal group to establish acute liver injury model. After 16 h,the blood of the mice was collected from the eyeballs,and their liver tissues were collected. The levels of alanine aminotransferase( ALT),aspartate aminotransferase( AST),superoxide dismutase( SOD),malondialdehyde( MDA) and glutathione peroxidase( GSH-Px) in the sera were determined by biochemical methods,and the contents of tumor necrosis factor-α( TNF-α),interleukin-1β( IL-1β) and interleukin-6( IL-6) in the liver tissues were determined with enzyme-linked immunosorbent assays( ELISA). [Results]Qiwei Jingganling significantly reduced the activities or content of ALT,AST and MDA in serum of mice with liver injury( P < 0. 05,P < 0. 01),increased the activities of SPD and GSH-Px( P < 0. 05,P < 0. 01) and down-regulated the expression levels of IL-1β,IL-6 and TNF-α in liver tissue( P < 0. 05,P < 0. 01).[Conclusions]Qiwei Jingganling has a good protection effect on CCl4-induced acute liver injury in mice,which may be related to the inhibition of oxidative stress and inhibition of inflammatory responses.

Protective Effect and Mechanism of Polysaccharides from Cordyceps cicadae on Acute Liver Injury Induced by D-GlaN in Mice

[Objectives]To observe the protective effect of Cordyceps cicadae polysaccharides on acute liver injury induced by D-galactosamine( D-GlaN) in mice,and to explore its mechanism. [Methods] Seventy-five male Kunming mice were randomly and evenly divided into 5 groups according to the digital table method: normal group( CK)( injected intraperitoneally with saline solution),model group( injected intraperitoneally with D-GlaN),low-dose C. cicadae polysaccharides group( administered with 0. 5 g/kg of C. cicadae polysaccharides solution by gavage),middle-dose C. cicadae polysaccharides group( administered with 1. 0 g/kg of C. cicadae polysaccharides solution by gavage) and high-dose C. cicadae polysaccharides group( administered with 2. 0 g/kg of C. cicadae polysaccharides solution by gavage). After 12 d of administration,the liver histopathological score,liver homogenate indexes( superoxide dismutase,SOD; malondialdehyde,MDA; glutathione peroxidase,GSH-Px; nitric oxide,NO) and serum markers( aspartate transaminase,AST; alanine transaminase,ALT; alkaline phosphatase,ALP; cholinesterase,CHE) of mice in each group were detected. The expression levels of nuclear factor-κB( NF-κB) and tumor necrosis factor-α( TNF-α) in liver tissues were detected by immunohistochemistry. [Results]The liver histopathological score and the MDA,NO,AST,ALT,ALP,NF-κB and TNF-α levels were significantly higher( P < 0. 05) and the SOD,GSH-Px and CHE levels were significantly lower( P <0. 05) in the model group compared with the normal group. Compared with those in the model group,the liver tissue histopathological scores in the low-,middle-and high-dose C. cicadae polysaccharides groups were all significantly reduced( P < 0. 05). With the increase of treatment dose,the liver tissue histopathological scores showed a significant decrease( P < 0. 05). Compared with the model group,the levels of MDA,NO,AST,ALT,ALP,NF-κB and TNF-α were significantly lower( P < 0. 05),and the levels of SOD,GSH-Px and CHE were significantly higher( P < 0. 05) in the low-,middle-and high-dose C. cicadae polysaccharides groups. With the increase of treatment dose,the levels of MDA,NO,AST,ALT,ALP,NF-κB and TNF-α declined significantly( P < 0. 05),while the levels of SOD,GSH-Px and CHE rose significantly( P < 0. 05). [Conclusions] C. cicadae polysaccharides have a significant protective effect on D-GlaN-induced acute liver injury in mice in a dose-dependent manner,and the mechanism may be related to the inhibition of NF-κB inflammatory signaling pathway.

Protective Effects of Flavonoids from Pteridium aquilinum on CCl_(4)-induced Acute Liver Injury in Mice

[Objectives]To explore the protective effects of flavonoids from Pteridium aquilinum(PAFL)on carbon tetracholoride(CCl_(4))-induced acute liver injury in mice and its potential mechanism.[Methods]All mice were randomly divided into four groups(n=10 in each),normal group,CCl_(4)group,CCl_(4)+PAFL groups[treated with PAFL(50 or 200 mg/kg)].Animal treatment was continued for 7 consecutive days.The blood was collected after injection of CCl_(4)for 24 h,and the liver tissue was removed from the mice and stored at-80℃.[Results]The PAFL(50 and 200 mg/kg)significantly inhibited the increase of aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels in serum caused by CCl_(4)treatment.PAFL administration not only increased the activity of antioxidant enzymes superoxide dismutase(SOD),Glutathione(GSH)and catalase(CAT)in mice,but also reduced the level of malondialdehyde(MDA).Meanwhile,PAFL administration decreased the expression of nuclear factor-kappa B(NF-κB)and Cyclooxygenase-2(COX-2)proteins and inhibited the release of pro-inflammatory factors tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β)and interleukin 6(IL-6).In addition,PAFL(200 mg/kg)treatment down-regulated extracellular regulated protein kinases(ERK)and c-Jun N-terminal kinase(JNK)protein levels in liver tissue.[Conclusions]These findings clearly indicate that the protective effects of PAFL on CCl_(4)-induced acute liver injury is related to its antioxidant and anti-inflammatory activity,which may be mediated by NF-κB and MAPKs signaling pathways.

Protective effects of C-phycocyanin on alcohol-induced acute liver injury in mice

Excessive alcohol consumption leads to liver disease. Extensive evidence suggests that C-phycocyanin(C-PC), a chromophore phycocyanobilin derived from Spirulina platensis, exerts protective eff ects against chemical-induced organ damage. In this study, we investigated whether C-PC could protect against ethanol-induced acute liver injury. Serum alanine aminotransferase(ALT), aspartate aminotransferase(AST), triglyceride(TG), total cholesterol(CHOL), low-density lipoprotein(LDL), liver homogenate malondialdehyde(MDA), superoxide dismutase(SOD) content were measured, and pathological examination of liver sections were examined. C-PC showed obvious inhibitory eff ects on serum ALT, AST, TG, CHOL, LDL and MDA, and SOD content significantly increased in the liver. The structure of hepatic lobules was clear, liver sinus returned to normal, and liver cell cords were arranged in neat rows. Cloudiness, swelling, inflammatory cell infiltration and spotty necrosis of liver cells were significantly reduced. Therefore, C-PC can significantly protect against ethanol-induced acute liver injury.

Elaborately engineering of lipid nanoparticle for targeting delivery of siRNA and suppressing acute liver injury

Small interfering RNA(siRNA)-based gene silencing has been considered as a potential therapy modality against inflammatory diseases.Nevertheless,the effective delivery of siRNA to desired destination still remains challenging due to poor stability,high molecular weight and negative charge.Currently,ionizable lipid nanoparticle(LNP)has been extensively used as vector for effective delivery of siRNA.Herein,we report a mannose-modified LNP(M-MC_(3) LNP@TNFα)loading tumor necrosis factorα(TNFα)siRNA for targeting liver macrophages,achieving effectively inhibit acute liver injury.The M-MC_(3) LNP@TNFαnot only increases the internalization of LNP by macrophages,but also enhances the gene silencing efficiency of TNFαin vitro.Additionally,the M-MC_(3) LNP@TNFαexhibits higher accumulation in liver of healthy mice than that of MC_(3) LNP@TNFα(un-modified LNP)owing to the targeting effect of mannose.As expected,the M-MC_(3) LNP@TNFαsignificantly suppresses the expression of TNFαand ameliorates liver damage in acute liver injury model.Such a LNP targeting siRNA delivery holds great potential for the treatment of diseases associated with liver in the future.

Lycium barbarum polysaccharides ameliorate canine acute liver injury by reducing oxidative stress,protecting mitochondrial function,and regulating metabolic pathways

The development of acute liver injury can result in liver cirrhosis,liver failure,and even liver cancer,yet there is currently no effective therapy for it.The purpose of this study was to investigate the protective effect and therapeutic mechanism of Lycium barbarum polysaccharides(LBPs)on acute liver injury induced by carbon tetrachloride(CCl_(4)).To create a model of acute liver injury,experimental canines received an intraperitoneal injection of 1 mL/kg of CCl_(4)solution.The experimental canines in the therapy group were then fed LBPs(20 mg/kg).CCl_(4)-induced liver structural damage,excessive fibrosis,and reduced mitochondrial density were all improved by LBPs,according to microstructure data.By suppressing Kelch-like epichlorohydrin(ECH)-associated protein 1(Keap1),promoting the production of sequestosome 1(SQSTM1)/p62,nuclear factor erythroid 2-related factor 2(Nrf2),and phaseⅡdetoxification genes and proteins downstream of Nrf2,and restoring the activity of anti-oxidant enzymes like catalase(CAT),LBPs can restore and increase the antioxidant capacity of liver.To lessen mitochondrial damage,LBPs can also enhance mitochondrial respiration,raise tissue adenosine triphosphate(ATP)levels,and reactivate the respiratory chain complexes I–V.According to serum metabolomics,the therapeutic impact of LBPs on acute liver damage is accomplished mostly by controlling the pathways to lipid metabolism.9-Hydroxyoctadecadienoic acid(9-HODE),lysophosphatidylcholine(Lyso PC/LPC),and phosphatidylethanolamine(PE)may be potential indicators of acute liver injury.This study confirmed that LBPs,an effective hepatoprotective drug,may cure acute liver injury by lowering oxidative stress,repairing mitochondrial damage,and regulating metabolic pathways.

Portulaca oleracea alleviates CCl4-induced acute liver injury by regulating hepatic S100A8 and S100A9

Objective: Acute liver injury(ALF) is a potential factor of many serious hepatopathies. Carbon tetrachloride(CCl4) is a possible environmental toxicant that can induce ALF. Portulaca oleracea(PO) is one of the most popular edible herbs and has several biological activities such as antioxidant, antimicrobial, antiinflammatory effects. We explored the significance of PO in regulating inflammatory function in animal models and cultured hepatocytes during liver damage caused by CCl4.Methods: The effect of PO on ALF was evaluated by CCl4-induced mice models in vivo. Hepatic levels of transaminase activities and inflammatory factors were examined. The gene and protein expression of S100A8 and S100A9 were measured by RT-PCR and Western blot analysis. Meanwhile, the efficacy of PO was certified by HepG2 cells in vitro. The transaminase activities, inflammatory factors, and the protein expression of S100A8 and S100A9 were also detected.Results: Animal tests showed that pretreatment with PO reduced the liver pathological tissue damage and the serum levels of ALT, AST, ALT and LDH, as well as reducing the pro-inflammatory cytokines(IL-1β, IL-6, TNF-a) secretion in CCl4-induced liver injury mice. Simultaneously, Hep G2 cells pretreated with PO exhibited a significant decrease in the activities of ALT and AST. Moreover, PO resulted in a significant downregulation of the pro-inflammatory markers S100A8, S100A9 gene and protein expression on CCl4induced acute liver injury was demonstrated entirely in vivo and vitro experiments.Conclusion: PO may down-regulate S100A8 and S100A9 and inhibit pro-inflammatory cytokines’ release,indicating a potential clinical effect for controlling the disease.

MALAT1-mediated EZH2 Recruitment to the GFER Promoter Region Curbs Normal Hepatocyte Proliferation in Acute Liver Injury

Background and Aims:The goal of this study was to investigate the mechanism by which the long noncoding RNA MALAT1 inhibited hepatocyte proliferation in acute liver injury(ALI).Methods:Lipopolysaccharide(LPS)was used to induce an ALI cellular model in HL7702 cells,in which lentivirus vectors containing MALAT1/EZH2/GFER overexpression or knockdown were introduced.A series of experiments were performed to determine their roles in liver injury,oxidative stress injury,and cell biological processes.The interaction of MALAT1 with EZH2 and enrichment of EZH2 and H3K27me3 in the GFER promoter region were identified.Rats were treated with MALAT1 knockdown or GFER overexpression before LPS induction to verify the results derived from the in vitro assay.Results:MALAT1 levels were elevated and GFER levels were reduced in ALI patients and the LPS-induced cell model.MALAT1 knockdown or GFER overexpression suppressed cell apoptosis and oxidative stress injury induced cell proliferation,and reduced ALI.Functionally,MALAT1 interacted directly with EZH2 and increased the enrichment of EZH2 and H3K27me3 in the GFER promoter region to reduce GFER expression.Moreover,MALAT1/EZH2/GFER was activated the AMPK/mTOR signaling pathway.Conclusion:Our study highlighted the inhibitory role of reduced MALAT1 in ALI through the modulation of EZH2-mediated GFER.

Antioxidant and Antiapoptotic Polyphenols from Green Tea Extract Ameliorate CCl4-Induced Acute Liver Injury in Mice

Objective To investigate the phenolic composition,antioxidant properties,and hepatoprotective mechanisms of polyphenols from green tea extract(GTP)in carbon tetrachloride(CCl4)-induced acute liver injury mouse model.Methods High-performance liquid chromatography was used to analyze the chemical composition of the extract.Antioxidant activity of GTP was assessed by O2∙-,OH∙,DPPH∙,and ferric-reducing antioxidant power(FRAP)assay in vitro.Sixty Kunming mice were divided into 6 groups including control,model,low-,medium-,and high-doses GTP(200,400,800 mg/kg)and vitamin E(250 mg/kg)groups,10 in each group.GTP and vitamin E were administered at a level of abovementioned doses twice per day for 7 days prior to exposure to a single injection of CCl4.Hepatoprotective effects of GTP were evaluated in a CCl4-induced mouse model of acute liver injury,using commercial enzyme linked immunosorbent assay kits,histopathological observation,terminal deoxynucleotidyl transferase-mediated dUTPNick-end labeling(TUNEL)assay and Western blot.Results GTP contained 98.56µg gallic acid equivalents per milligram extract total polyphenols,including epicatechingallate,epigallocatechin gallate,epicatechin,and epigallocatechin.Compared with the model group,low-,medium-,or high doses GTP significantly decreased serum levels of alanine aminotransferase and aspartate transaminase(P<0.01).Histopathological observation confirmed that pretreatment of GTP prevented swelling and necrosis in CCl4-exposed hepatocytes.Hepatoprotective effects of low-,medium-,and high-dose GTP were associated with eliminating free radicals and improving superoxide dismutase,catalase,and glutathione peroxidase activity in the liver.Additionally,low-,medium-,and high-dose GTP decreased cell apoptosis in the CCl4-exposed liver(P<0.01).Phosphorylated nuclear factor kappa-B(NF-κB),p53,Bcl-2 associated x protein/B-cell lymphoma/leukemia-2 gene,cytochrome C,and cleaved caspase-3 levels were downregulated compared with the model group(P<0.01).Conclusion GTP achieves hepatoprotective effects by improving hepatic antioxidant status and preventing cell apoptosis through caspase-3-dependent signaling pathways.

Protective effects of Polygonatum sibiricum against CCl_(4)-induced acute liver injury in rats through oxidative stress and mitochondrial apoptotic pathways

In the present study,we aimed to investigate the hepatoprotective effect of Chinese herbal medicine Polygonatum sibiricum(PS).In this study,a rat acute liver injury(ALI)model was established by a single intraperitoneal injection of 50%CCl_(4) oil solution,and the rats were treated intragastrically with Polygonatum sibiricum aqueous extract(PSAE).The results showed that PSAE significantly decreased the serum levels of ALT,AST and ALP,increased the activities of glutathione(GSH)and superoxide dismutase(SOD),decreased malondialdehyde(MDA)activity in hepatic tissue,and decreased the reactive oxygen species(ROS)level in hepatocytes.The expressions of Nrf2,NQO-1,HO-1,Bcl-2,Bcl-x L mRNA,and HO-1 proteins were elevated,and the expression of p53 mRNA was decreased.In conclusion,PSAE exerted a powerful protective action against CCl_(4)-induced ALI in rats via effectively regulating the expressions of Nrf2-Keap1-ARE related genes and proteins,and inhibiting hepatocyte apoptosis.These outcomes provided evidence that PS had apparent hepatoprotective effect.

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.

Impact of non-alcoholic fatty liver disease on coronavirus disease 2019: A systematic review

BACKGROUND Many studies have revealed a link between non-alcoholic fatty liver disease(NA-FLD)and coronavirus disease 2019(COVID-19),making understanding the relationship between these two conditions an absolute requirement.AIM To provide a qualitative synthesis on the currently present data evaluating COVID-19 and NAFLD.METHODS This systematic review was conducted in accordance with the guidelines pro-vided by preferred reporting items for systematic reviews and meta-analyses and the questionnaire utilized the population,intervention,comparison,and outcome framework.The search strategy was run on three separate databases,PubMed/MEDLINE,Scopus,and Cochrane Central,which were systematically searched from inception until March 2024 to select all relevant studies.In addition,ClinicalTrials.gov,Medrxiv.org,and Google Scholar were searched to identify grey literature.RESULTS After retrieval of 11 studies,a total of 39282 patients data were pooled.Mortality was found in 11.5%and 9.4%of people in NAFLD and non-NAFLD groups.In all,23.2%of NAFLD patients and 22%of non-NAFLD admissions diagnosed with COVID-19 were admitted to the intensive care unit,with days of stay varying.Ventilatory support ranged from 5%to 40.5%in the NAFLD cohort and from 3.1%to 20%in the non-NAFLD cohort.The incidence of acute liver injury showed significance.Clinical improvement on days 7 and 14 between the two classifications was significant.Hospitalization stay ranged from 9.6 days to 18.8 days and 7.3 days to 16.4 days in the aforementioned cohorts respectively,with 73.3%and 76.3%of patients being discharged.Readmission rates varied.CONCLUSION Clinical outcomes except mortality consistently showed a worsening trend in patients with NAFLD and concomitant COVID-19.Further research in conducting prospective longitudinal studies is essential for a more powerful conclusion.