ABSTRACT
SUMMARY: Paracetamol (known as acetaminophen, or APAP) poisoning causes acute liver damage that can lead to organ failure and death. We sought to determine that APAP overdose can augment tumor necrosis factor-alpha (TNF-α)/ nuclear factor kappa B (NF-kB)/induced nitic oxide synthase (iNOS) axis-mediated hepatotoxicity in rats, and the anti-inflammatory polyphenolic compounds, quercetin (QUR) plus resveratrol (RES) can ameliorate these parameters. Therefore, we induced acute hepatotoxicity in rats using APAP overdose (2 g/kg, orally) and the protective group of rats were treated with 50 mg/kg QUR plus 30 mg/kg RES for one week before APAP ingestion. Animals were killed at day 8. APAP poisoning caused the induction of hepatic tissue levels of TNF-α, NF-kB, and iNOS, which were significantly (p<0.05) decreased by QUR+RES. QUR+RES, also inhibited liver injury biomarkers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, a link between liver injury and TNF-α /NF-kB / iNOS axis mediated hepatotoxicity was observed. Thus, the presented data backing the conclusion that intoxication by paracetamol increases TNF-α / NF-kB / iNOS axis -mediated hepatotoxicity, and is protected by a combination of quercetin and resveratrol.
El envenenamiento por paracetamol (conocido como acetaminofeno o APAP) causa daño hepático agudo que puede provocar una insuficiencia orgánica y la muerte. El objetivo de este trabajo fue determinar si la sobredosis de APAP puede aumentar la hepatotoxicidad mediada por el eje del factor de necrosis tumoral alfa (TNF-α)/factor nuclear kappa B (NF-kB)/óxido nítico sintasa inducida (iNOS) en ratas, y si el polifenólico antiinflamatorio compuesto por quercetina (QUR) más resveratrol (RES) pueden mejorar estos parámetros. Por lo tanto, inducimos hepatotoxicidad aguda en ratas usando una sobredosis de APAP (2 g/kg, por vía oral). El grupo protector de ratas se trató con 50 mg/ kg de QUR más 30 mg/kg de RES durante una semana antes de la ingestión de APAP. Los animales se sacrificaron el día 8. El envenenamiento con APAP en el tejido hepático provocó la inducción de niveles de TNF-α, NF-kB e iNOS, que se redujeron significativamente (p<0,05) con QUR+RES. QUR+RES, también inhibió los biomarcadores de daño hepático, la alanina aminotransferasa (ALT) y el aspartato aminotransferasa (AST). Además, se observó una relación entre la lesión hepática y la hepatotoxicidad mediada por el eje TNF-α /NF-kB/iNOS. Por lo tanto, los datos presentados respaldan la conclusión de que la intoxicación por paracetamol aumenta la hepatotoxicidad mediada por el eje TNF-α /NF-kB / iNOS, y está protegida por una combinación de quercetina y resveratrol.
Subject(s)
Animals , Rats , Quercetin/administration & dosage , Chemical and Drug Induced Liver Injury, Chronic/drug therapy , Resveratrol/administration & dosage , Acetaminophen/toxicity , Acute Disease , NF-kappa B/antagonists & inhibitors , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Rats, Sprague-Dawley , Nitric Oxide Synthase/antagonists & inhibitors , Protective Agents , Drug Therapy, Combination , Drug OverdoseABSTRACT
OBJECTIVE@#To investigate the protective effects of Ginkgo biloba extract(GBE) on paracetamol(APAP)-induced acute hepatic injury in mice and its mechanism.@*METHODS@#Thirty mice were randomly divided into control group, model group, GBE low, medium and high-dose(50,100,and 200 mg·kg)groups,with 6 mice in each group. All mice except control group were administered with APAP(300 mg/kg)for one time by intraperitoneal injection. The mice in GBE low, medium and high-dose groups were intragastric administered with GBE for 2 d consecutively, then samples were harvested for analysis. The appearance and pathology of liver were observed. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in serum and the levels of superoxide dismutase (SOD), myeloperoxidase(MPO), glutathione (GSH) and malondialdehyde (MDA) in hepatic tissue were measured. Western blot was used to detect the protein expressions of Nrf2 and HO-1.@*RESULTS@#Compared with control group, in model group, the appearance and pathology of liver were bad, the levels of ALT,AST,TNF-α and IL-6 in serum were increased significantly(<0.01),the levels of GSH and SOD were decreased while the levels of MDA and MPO were increased in hepatic tissue(<0.01), the expressions of Nrf2 and HO-1 were increased in hepatic tissue(<0.05). Compared with model group, in GBE groups, the appearance and pathology of liver were improved, the levels of ALT,AST,TNF-α and IL-6 in serum were decreased significantly(<0.01), the levels of GSH and SOD were increased while the levels of MDA and MPO were decreased in hepatic tissue(<0.01), the expression of Nrf2 and HO-1 were increased in hepatic tissue(<0.05). The high-dose of GBE possessed the most obvious treatment effect among them.@*CONCLUSIONS@#GBE may play a protective role in APAP-induced acute hepatic injury through Nrf2/HO-1 pathway.
Subject(s)
Animals , Mice , Acetaminophen , Alanine Transaminase , Aspartate Aminotransferases , Chemical and Drug Induced Liver Injury , Ginkgo biloba , Liver , Malondialdehyde , Oxidative Stress , Plant ExtractsABSTRACT
Hepatic disease is one of the high-prevalence diseases in China, of which gastrointestinal bleeding is a common complication treated by proton pump inhibitors. Vonoprazan is a novel proton pump inhibitor which acts better than lansoprazole in pharmacokinetics and pharmacodynamics. In this study, the pharmacokinetics of vonoprazan was compared between acute hepatic injury and normal condition in rats. Results showed that the exposure (AUC) of vonoprazan was significantly higher in rats with acute hepatic injury than in normal rats, and the metabolites formation rates of vonoprazan also slowed down, which might be due to the change of activity of enzymes and transporters. This find may provide a theoretical basis for the dose regulation of vonoprazan in patients with hepatic injury.
ABSTRACT
OBJECTIVE:To elucidate the efficacy and mechanism of Hugan tablets in hepatoprotective effects from perspective of metabolic pathways. METHODS:36 male rats were randomly divided into normal group (0.5%sodium carboxymethyl cellu-lose),model group(0.5%sodium carboxymethyl cellulose)and Hugan tablets group(1.7 g/kg),12 in each group,intragastrically administrated once a day,for 9 d. After 1 h of last administration,rats in model group and Hugan tablets group were intraperitone-ally injected 50%CCl4 peanut oil solution 1 mL/kg to induce liver injury. After 24 h of modeling,malondialdehyde(MDA),super-oxide dismutase(SOD),glutathione peroxidase(GSH-Px)levels in liver tissue of rats were detected. Nuclear magnetic resonance spectroscopy(1H-NMR)metabolomics technique was adopted to establish the serum and liver metabolite profiles of rats,and the ef-fects of Hugan tablets on changes of metabolic profile and potential biomarkers in serum and liver of rats with CCl4-induced acute liver injury were analyzed. RESULTS:Compared with normal group,MDA level in liver tissue of rats in model group was signifi-cantly increased(P<0.05),SOD and GSH-Px levels were significantly reduced(P<0.05). Both body physiology and material me-tabolism of rats were obviously changed,and levels of 11 metabolic potential biomarkers in serum and 14 metabolic potential bio-markers in liver were significantly increased/decreased (P<0.05). Compared with model group,MDA level in liver tissue in Hugan tablets group was significantly reduced(P<0.05),SOD and GSH-Px levels were significantly increased(P<0.05). Serum and liver metabolism tended to be normal,6 metabolic potential biomarkers(isoleucine,leucine,3-hydroxybutyrate,acetone,ace-toacetate,choline) in serum and 8 metabolic potential biomarkers (3-hydroxybutyrate,alanine,glutamate,pyruvate,succinate, choline,lactate,glucose)in liver got significant callback(P<0.05). CONCLUSIONS:The hepatoprotective mechanism of Hugan tablets may be associated with antioxidative stress and regula-tion of lipid metabolism,glucose metabolism and amino acid metabolism.
ABSTRACT
Aim: To describe a case of acute hepatic injury related to the use of Grifola frondosa in a patient with colon cancer. Case Presentation: Patient is a 67 year old female with stage IV poorly differentiated adenocarcinoma of the colon, who presented with epigastric pain one month after resection of her primary tumor. A staging PET scan revealed metastasis to regional lymph nodes without solid organ involvement. Her home medications include longstanding amlodipine and losartan, and a recently started Grifola frondosa derivative. Her laboratory data was significant only for acute transaminitis (AST:967 U/L, ALT:768 U/L) without hyperbilirubinemia. Alcohol, acetaminophen, and a viral panel (EBV, CMV, hepatitis A/B/C) were all negative. A CT scan revealed heterogenous liver parenchyma without focal lesions. A subsequent liver biopsy demonstrated active portal inflammation with eosinophilic infiltration. Discussion: The etiologies of significant acute transaminitis include viral hepatitis, ischemic liver injury, acetaminophen toxicity and drug-induced liver injury (DILI). Viral and ischemic hepatitis and acetaminophen toxicity were excluded based on laboratory analysis and imaging studies. Liver biopsy findings demonstrating the characteristic eosinophilic infiltration of a drug reaction favored DILI as the etiology of transaminitis in this case. With a RUCAM score of 7 calculated based on history, clinical course, and objective data, DILI was concluded to be probably attributed to the patient’s recent use of the Grifola frondosa extract. Conclusion: A diagnosis of drug induced liver injury probably secondary to the use of Grifola frondosa extract was made after excluding all other causes of significant acute transaminitis.
ABSTRACT
Objective To discuss the protection mechanism of total saponins from Panax japonicus on acute hepatic injury induced by carbon tetrachloride. Methods HepG2 cells were used to establish CCl4-induced liver cell injury model in vitro experiments. Mouse model of acute liver injury was caused by 1%CCl4 oil on Balb/c. Mice were randomly divided into normal group, model group and medicine group. Mice in the medicine group were given a gavage with 20 mL/kg total saponins from Panax japonicus, while mice in the other two groups were given a gavage with the same amount of stroke-physiological saline solution. MTT method was used to detect the activity of hepatic cells. The pathological changes of mouse liver were examined by HE staining. RT-PCR was used to detect changes in the expression of transforming growth TGF-β, TNF-α, and TLR4 mRNA. Results Compared with normal group, less hepatic cells survived in model group (P<0.01);compared with model group, more hepatic cells survived in medicine group (P<0.01). HE staining showed that damages in liver tissues of medicine group significantly improved than those in model group. RT-PCR results showed that the levels of TGF-β, TNF-α, and expression of TLR4 mRNA increased more significantly than those in model group;the expression of TGF-β, TNF-α, and TLR4 mRNA in medicine group decreased more significantly than those in model group, with statistical significance (P<0.01). Conclusion The total saponins from Panax japonicus has a protective effect on liver injury induced by carbon tetrachloride.
ABSTRACT
@#Objective To explore the effect of Curcumae on acute hepatic injuried mice.Methods The model mice of acute hepatic injury were established with intraperitoneal injecting 0.2% carbon tetrachloride (CCl4) 0.2 ml/10mg. 48 mice were randomized into 6 groups: model group, control group, Ganlixin group (25 mg/kg) and three treating groups of Curcumae which were administrated by gavage at the doses of 2.5 g/kg, 5 g/kg, 10 g/kg once everyday.7 d later, all mice were put to death. The liver index, the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) in serum, the activities of superoxide dismutase (SOD) and the content of malondialdehyde (MDA) in hepatic tissue were observed. Pathological change was observed under HE staining. Results Compared with the model group, Curcumae could decrease the liver index and the activities of ALT and AST in serum, MDA in hepatic tissue significantly (P<0.05), and increase the activities of SOD (P<0.05). The pathological changes were less in three treating groups than that of the models. Conclusion Curcumae can protect the liver from acute hepatic injuried induced with CCl4 in mice.
ABSTRACT
Objective To explore the protective effects of extraction of Glycyrrhiza uralensis Fisch. (GC) on CCl4 induced acute hepatic injury in mice. Methods Acute hepatic injury model was made by CCl4. Fifty mice were divided into 5 groups (normal control group, CCl4 model group, bifendate group, low and high dose of GC group) and administrated for 7 days. The levels of ALT, AST, ALP, LPH, TP, ALB, GLB in serum and the activities of SOD, MDA in liver tissue were detected. Results The activities of ALT, AST and the level of MDA in GC group were significantly decreased, and the activity of SOD were significantly increased compared with the model group (P
ABSTRACT
Objective To study the effect of extract of cockroach on animals with acute hepatic injury and its antiviral action in vitro. Methods The animal models with hepar injury were established by CCl4, bcg vaccine and lipopolysaccharide (LPS) . And the activities of ALT and AST in serum were measured. Serum of ducks was separated after cockroach extract was administrated. The serum was added to the culture fluid of HBV-DNA transfected hepatic cancer cells-HepG2. Results After the cockroach extract was administrated, the activities of ALT and AST in mouse serum were reduced. Both the therapeutic indexes of cockroach extract and lamivudine were larger than 2. Conclusions Cockroach extract can improve the liver function of animals with acute hepatic injury, and inhibit the secretion of ALT and AST in serum.
ABSTRACT
Objective To explore the roles and clinical significance of glutamine(GLN) in carbon tetrachloride(CCl_(4)) induced acute hepatic injury.Methods The SD rats were divided into model group,GLN pretreated group and control group.The animal model was established by CCl_(4) intraperitoneal injection.GLN at dose of 1 g/kg was intragastrically administrated for 7 d before intraperitoneal injection of CCl_(4) in the rats of GLN pretreated group.The rats were executed 4,8,12,16,24 h after injure.To evaluate the hepatic injury,the serum alanine aminotransferase(ALT) and aspartate aminotransferase(AST) were detected by automatic biochemistry analysator.The liver tissue was observed by light microscope and transmission electron microscope(TEM).The expression of nuclear factor-?B(NF-?B) was detected by immunohistochemistry and the tumor necrosis factor?(TNF-?) was detected by reverse transcription polymerase chain reaction(RT-PCR).The apoptosis of hepatocyte was detected by TUNEL.The oncosis index was detected by TEM.Results The levels of ALT,AST,NF-?B,TNF-? mRNA in model group were apparently elevated as compared to control group(P
ABSTRACT
Objective To investigate the correlation of oncosis and TNF-? in D-galactosamine (D-GalN) induced acute hepatic injury. Methods Acute hepatic injury model was induced by D-GalN in 24 SD rats, and 12 rats served as control. At 4, 8, 12, 16, 20, 24 h after intraperitoneal injection of D-GalN, the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, and the tumor necrosis factor-? (TNF-?) in liver tissue were measured. The pathological changes of liver and the oncosis of hepatocytes were observed by TEM. Results In acute hepatic injury, the levels of ALT, AST, TNF-? mRNA, OI were higher than that of control group (P
ABSTRACT
Objective To investigate the hepatoprotective effect of Propolis alcohol-extract (PAE) against acetaminophen (APAP)-induced acute hepatic damage in mice and to explore the possible mechanism.Methods Sixty-three C57BL/6 MT(-/-)mice were equally randomized into 9 groups.The normal control group and the model group received gastric gavage of normal saline (20 mL?kg-1),four PAE groups were given PAE in the dose of 12.5,25,50 and 100 mg?kg-1 respectively,alcohol +APAP group and alcohol control group received 20 %alcohol 20 mL?kg-1 and PAE control group was given PAE in the dose of 100 mg?kg-1 qd,for 4 consective days.Thirty miniutes after last administration,the mice in the normal control group,PAE control group and alcohol control group received saline 10 mL?kg-1,and the mice in other groups received APAP 380 mg?kg-1 to induce acute hepatic injury.The activities of serum alanine aminotransferase (ALT),aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were determined,and the liver tissues were collected for histopathological assessment by HE staining under light microscope.The ratio of glutathione (GSH) and oxidized glutathione (GSSG),and the content of GSH,GSSG and malondialdehyde (MDA) in liver homogenate were also measured.Results Compared with the model group,PAE could markedly decrease serum ALT,AST and LDH activity,reduce the MDA level in liver homogenate,and increase hepatic GSH content and the ratio of GSH/GSSG in the liver homogenate.The hepatic histopathological changes in liver were also significantly ameliorated.In PAE control group,GSH content and the ratio of GSH/GSSG were also increased.However,the above indexes remained unchanged in alcohol control group.Conclusion The propolis alcohol-extract can prevent the liver from PAP-induced acute hepatic injury.
ABSTRACT
BACKGROUND/AIMS: Tc-DTPA-galactosylated serum albumin (GSA) is a new liver imaging agent that specifically binds to asialoglycoprotein receptor, which resides exclusively on the plasma membrane of mammalian hepatocytes. To evaluate the usefulness of hepatic scintigraphy with Tc-GSA in the assessment of hepatic function, we have investigated serial changes in organ uptakes of Tc-GSA in mice with thioacetamide-induced hepatic injury and compared to changes in histology or levels of hepatic enzymes. MATERIALS AND METHODS: Acute hepatic injuries were induced by intraperitoneal injection of thioacetamide in ICR (Institute of Cancer Research) mice. Hepatic injuries were serially assessed by either light microscopic examination of liver slices or measurement of hepatic enzymes. The biodistribution of Tc-GSA was measured in liver and each excised organs using gamma counter. RESULTS: Hepatic injuries in light microscopic examination were not evident at 12 hours after injection of thioacetamide but resulted in maximal centrilobular necrosis and inflammation at 24 hours. These histologic changes were progressively improved upto 72 hours. Studied hepatic enzymes were elevated at 6 hours and reached to maximal level at 24 hours after administration of thioacetamide and declined progressively after then. Hepatic uptake of Tc-GSA was lowest at 6 hours after administration of thioacetamide and serially recovered until 72 hours. CONCLUSION: The degree in the decrease of hepatic uptake of Tc-GSA was precedent to either histologic changes or elevation of hepatic enzymes and correlated with the degree of hepatic daneges in acute hepatic injury. These findings suggest that hepatic scintigraphy using Tc-GSA can be used to detect early changes and serial assessment of hepatic function in acute hepatic injury.
Subject(s)
Animals , Mice , Asialoglycoprotein Receptor , Cell Membrane , Hepatocytes , Inflammation , Injections, Intraperitoneal , Liver , Necrosis , Radionuclide Imaging , Serum Albumin , ThioacetamideABSTRACT
BACKGROUND/AIMS: Tc-DTPA-galactosylated serum albumin (GSA) is a new liver imaging agent that specifically binds to asialoglycoprotein receptor, which resides exclusively on the plasma membrane of mammalian hepatocytes. To evaluate the usefulness of hepatic scintigraphy with Tc-GSA in the assessment of hepatic function, we have investigated serial changes in organ uptakes of Tc-GSA in mice with thioacetamide-induced hepatic injury and compared to changes in histology or levels of hepatic enzymes. MATERIALS AND METHODS: Acute hepatic injuries were induced by intraperitoneal injection of thioacetamide in ICR (Institute of Cancer Research) mice. Hepatic injuries were serially assessed by either light microscopic examination of liver slices or measurement of hepatic enzymes. The biodistribution of Tc-GSA was measured in liver and each excised organs using gamma counter. RESULTS: Hepatic injuries in light microscopic examination were not evident at 12 hours after injection of thioacetamide but resulted in maximal centrilobular necrosis and inflammation at 24 hours. These histologic changes were progressively improved upto 72 hours. Studied hepatic enzymes were elevated at 6 hours and reached to maximal level at 24 hours after administration of thioacetamide and declined progressively after then. Hepatic uptake of Tc-GSA was lowest at 6 hours after administration of thioacetamide and serially recovered until 72 hours. CONCLUSION: The degree in the decrease of hepatic uptake of Tc-GSA was precedent to either histologic changes or elevation of hepatic enzymes and correlated with the degree of hepatic daneges in acute hepatic injury. These findings suggest that hepatic scintigraphy using Tc-GSA can be used to detect early changes and serial assessment of hepatic function in acute hepatic injury.
Subject(s)
Animals , Mice , Asialoglycoprotein Receptor , Cell Membrane , Hepatocytes , Inflammation , Injections, Intraperitoneal , Liver , Necrosis , Radionuclide Imaging , Serum Albumin , ThioacetamideABSTRACT
AIM: To study the protective effects of Xiaoyan Lidan Tablet(Herba Andrographis,Herba Rabdosiae serrae,Radix Sophorae Flavescentis,etc) on acute hepatic injury in rats. METHODS: Acute hepatic injury was induced by intraperitoneal(ip) injection of carbon tetrachloride and D-galactosamine,respectively.The levels of ALT,AST,ALP,TBA,total bilirubin(T-Bil),total protein (TP) and albumin(ALB) in serum were analyzed.The body weight,liver weight,spleen weight and thymus weight of each rat were measured.The hepatic glycogen content was analyzed individually.Liver tissue pathology was observed. RESULTS: Xiayan Lidan Tablet can decrease ALT,AST,ALP,TBA and T-Bil in serum,reduce necrosis in pathological observation. CONCLUSION: Xiaoyan Lidan Tablet gives the protective effects to acute hepatic injury induced by CCl_4 and D-Gal in rats.
ABSTRACT
OBJECTIVE:To study the protective effect of Mogrosides on experimental liver injury in mice. METHODS: Acute hepatic injury model was induced by CCl4 in mice, and the immunological hepatic injury model was induced in mice by bacillus calmette-guerin (BCG) and lipopolysaccharide (LPS). The activities of ALT and AST in serum, SOD activity in liver tissue and content of MDA in the liver tissue were investigated; and the histological changes of liver were observed. RESULTS: Mogroside could decrease the serum activities of ALT and AST in mice with acute hepatic injury or immunological hepatic injury, increase the activity of SOD but decrease MDA content in liver tissue of mice with immunological hepatic injury, and it could lessen the histological changes of liver. CONCLUSION: Mogroside showed protective effect on mice with acute hepatic injury or immunological hepatic injury. The mechanism might be attributed to its action against lipid peroxidation.
ABSTRACT
Objective: To study the protective effects of polypeptide-Fe on acute hepatic injury induced by CCl4 in mice. Method:Mice model of acute hepatic injury was set up by CCl4 ig (50mg/kg?d ). and fed with polypeptide-Fe 67.5 mg/kg?d, 675 mg/kg?d and 2 025 mg/kg?d for 30 d respectively. The effects on serum ALT, AST, and ALP and liver TG, TC, GSH, MDA, and SOD avtivities were observed. Results: Polypeptide-Fe decreased the activities of ALT, AST, and ALP in serum and the levels of TG, TC, and MDA in liver, and increased the level of GSH in liver. Middle dosage group of polypeptide-Fe was the most effective one. Conclusion:Polypeptide-Fe showed significant antioxidant ability in protecting acute hepatic injury induced by CCl4 in mice.