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 pharmacolog...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.展开更多
OBJECTIVE Acetaminophen(APAP),also known as paracetamol,is a commonly used antipyretic,anal⁃gesic and anti-inflammatory drug.However,during the use of APAP for more than half a century,people have not only used APAP t...OBJECTIVE Acetaminophen(APAP),also known as paracetamol,is a commonly used antipyretic,anal⁃gesic and anti-inflammatory drug.However,during the use of APAP for more than half a century,people have not only used APAP to fight diseases but have also suffered the adverse effects brought about by APAP for more than half a cen⁃tury.The most serious adverse reaction to APAP is hepatotoxicity caused by overdose or long-term use.In Chinese tra⁃ditional medicine,chrysanthemums have the functions of dispelling wind,dissipating heat,clearing the liver and improv⁃ing eyesight.Although the chrysanthemum variety named Bianliang ziyu from Kaifeng is not a medicinal variety,it has good value for medicine and food.The aim of this study was to investigate the protective effect of Bianliang Ziyu extract(BZE)on APAP-damaged rats and the potential molecular mechanism.METHODS Male Sprague-Dawley rats(200-220 g)were intragastrically administered BZE(110,220 and 440 mg·kg^-1)for 8 d.On the ninth day,APAP(800 mg·kg^-1)was administered intragastrically to the rats 0.5 h after BZE administration to induced drug-induced liver injury.The serum and liver samples were collected after 24 h.The levels of alanine aminotransferase(ALT),aspartic aminotransferase(AST),reactive oxygen species(ROS),malondialdehyde(MDA),superoxide dismutase(SOD)and glutathione(GSH)in serum and liver tissue of rats were detected by kit method.HE staining was used to observe the histopathological changes in the liver of rat.The effects of BZE on the expression of the oxidative stress related proteins and the mitochondrial biosyn⁃thesis related proteins were detected by Western blot.RESULTS The results showed that BZE significantly reduced the levels of ALT,AST,MDA and ROS and increased the levels of GSH and SOD caused by APAP.Moreover,BZE increased phosphorylation of AMP-activated protein kinase(AMPK)and glycogen synthase kinase 3β(GSK3β),promoted the nuclear translocation of nuclear factor-erythroid 2-related factor 2(Nrf2).BZE also upregulated the expression of mitochondrial biosynthesis related proteins such as peroxisome proliferator-activated receptorγ(PPAR-γ),peroxisome proliferator-activated receptorγcoactivator-1α(PGC-1α),mitochondrial transcription factor(TFAM)and nuclear respira⁃tory factor 1(NRF1).CONCLUSION BZE alleviates APAP-induced liver injury in rats by inhibiting oxidative stress via GSK3β-Nrf2 signaling and the mitochondrial biosynthesis pathway mediated by AMPK.展开更多
AIM To evaluate the safety and efficacy of the bioartificial liver support system in canines with acute liver failure (ALF). METHODS Nine canines with acute liver failure by acetaminophen induced received TECA Ⅰ...AIM To evaluate the safety and efficacy of the bioartificial liver support system in canines with acute liver failure (ALF). METHODS Nine canines with acute liver failure by acetaminophen induced received TECA Ⅰ bioartificial liver support system (BALSS) from Hong Kong TECA LTD Co. Blood was perfused through a hollow fiber tube containing (1 2)×10 10 the porcine hepatocytes. In contrast, another 10 canines with acute liver failure by Acetaminophen received drugs. Each treatment lasted 6 hours. RESULTS BALSS treatment resulted in beneficial effects for acetaminophen induced ALF canines with survival and with the recovery of the liver functions and tissues, and plasma ammonia decreased from 135 9μmol/L ± 17 5μmol/L to 65 7μmol/L ± 22 0μmol/L , 32 5μmol/L ± 8 8μmol/L , GPT from 97 8U/L ± 8 7U/L to 64 8U/L ± 11 9U/L , 19 0U/L ± 6 3U/L , GOT from 103 0U/L ± 16 7U/L to 75 7U/L ± 19 6U/L , 26 5U/L ± 5 0U/L , and AKP from 158 3U/L ± 12 1U/L to 114 5U/L ± 19 8U/L , 43 8U/L ± 5 6U/L during and after the treatment. In contrast, 10 ALF canines in both the drug and control groups died 1 or 2 days after treatment. CONCLUSION TECA 1 artificial liver support system is safe and efficacious for canines with acute liver failure.展开更多
AIM: To explore the mechanism of protection against acetaminophen-induced acute liver injury by Liuweiwuling tablets.METHODS: Intraperitoneal injections of acetaminophen(250 mg/kg) were used to induce acute liver inju...AIM: To explore the mechanism of protection against acetaminophen-induced acute liver injury by Liuweiwuling tablets.METHODS: Intraperitoneal injections of acetaminophen(250 mg/kg) were used to induce acute liver injury in male C57BL/6 mice.A total of 24 healthy mice were randomly assigned to two groups: an acute liver injury group(control group) and a Liuweiwuling tablet group.Mice were given Liuweiwuling tablets or a vehicle(PBS) orally prior to the administration of acetaminophen.Serum alanine aminotransferase(ALT) and aspartate aminotransaminase(AST) levels were measured at different time points within one week,and pathological examinations of liver tissues were performed 36 h after induction of acute liver injury.Serum inflammatory cytokines,such as high mobility group box protein B1(HMGB1),tumor necrosis factor(TNF)-α and interleukin IL-1b,were detected using an ELISA method according to the manufacturer's instructions.Hepatic morphological changes at 36 h were assessed by hematoxylin and eosin staining.Expression of proliferating cell nuclear antigen(PCNA) in liver tissue was determined by Western blot analysis.The m RNA levels of hepatocyte proliferation markers(PCNA,Cyclin D1 and p21) were detected by real-time quantitative reverse transcription-polymerase chain reaction.RESULTS: The levels of ALT/AST in the Liuweiwuling tablet group were decreased significantly at 6,12 and 24 h compared to that of the control group(654.38 ± 120.87 vs 1566.17 ± 421.64,1154.18 ± 477.72 vs 4654.84 ± 913.71 and 935.13 ± 252.34 vs 4553.75 ± 727.37,P < 0.01).Serum HMGB1 levels at 6 and 12 h for the Liuweiwuling tablet group were significantly lower than those of the control group(23.49 ± 3.89 vs58.6 ± 3.65,61.62 ± 13.07 vs 27.32 ± 5.97,P < 0.01).Furthermore,serum TNF-α and IL-1b levels at 12 h in the Liuweiwuling tablet group were also significantly lower than those of the control group(299.35 ± 50.61 vs 439.03 ± 63.59,57.42 ± 12.98 vs 160.07 ± 49.87,P < 0.01).Centrilobular necrosis was evident in liver tissue of mice with acetaminophen-induced acute liver injury,but was almost abolished in the Liuweiwuling tablet group.The expression levels of PCNA and Cyclin D1 were up-regulated in liver tissue in the Liuweiwuling tablet group(321.08 ± 32.87 vs 157.91 ± 21.52,196.37 ± 25.39 vs 68.72 ± 11.27,P < 0.01); however,expression of p21 in liver tissue was downregulated compared to that of the control group(40.26 ± 9.97 vs 138.24 ± 13.66,P < 0.01).CONCLUSION: Liuweiwuling tablets can attenuate acute liver injury by decreasing inflammatory cytokine(HMGB1,TNF-α and IL-1b) levels and promoting liver regeneration.展开更多
Objective:To investigate and compare the hepatoprotective effects of crude ethanolic and aqueous extracts of Phyllanthus acidus（L.） Skeels（P.acidus） leaves on acetaminophen（APAP） and thioacetamide（TAA） induced...Objective:To investigate and compare the hepatoprotective effects of crude ethanolic and aqueous extracts of Phyllanthus acidus（L.） Skeels（P.acidus） leaves on acetaminophen（APAP） and thioacetamide（TAA） induced liver toxicity in wistar rats.Silymarin was the reference hepatoprotective agent.Methods:In two different sets of experiments,the P.acidus extracts （200 and 400 mg/kg,body weight） and silymarin（100 mg/kg,body weight） were given orally for 7 days and a single dose of APAP（2 g/kg,per oral） or TAA（100 mg/kg,subcutaneous） were given to rats.The level of serum aspartate transaminase（AST）,alanine transaminase（ALT）,alkaline phosphatase（ALP）,total bilirubin and total protein were monitored to assess hepatotoxicity and hepatoprotection.Results:APAP or TAA administration caused severe hepatic damage in rats as evident from significant rise in serum AST,ALT,ALP,total bilirubin and concurrent depletion in total serum protein.The P.acidus extracts and silymarin prevented the toxic effects of APAP or TAA on the above serum parameters indicating the hepatoprotective action.The aqueous extract was found to be more potent than the corresponding ethanolic extract against both toxicants.The phenolic and flavonoid content（175.02±4.35 and 74.68±1.28,respectively） and 2,2-diphenyl-1- picrylhydrazil（DPPH）[IC<sub>50</sub>=（33.2±0.31）μg/mL]scavenging potential was found maximum with aqueous extract as compared to ethanolic extract.Conclusions:The results of present study suggests that the aqueous extract of P.acidus leaves has significant hepatoprotective activity on APAP and TAA induced hepatotoxicity,which might be associate with its high phenolic and flavonoid content and antioxidant properties.展开更多
AIM:To explore the effects of curcumin(CMN)on hepatic injury induced by acetaminophen(APAP)in vivo.METHODS:Male mice were randomly divided into three groups:groupⅠ(control)mice received the equivalent volumes of phos...AIM:To explore the effects of curcumin(CMN)on hepatic injury induced by acetaminophen(APAP)in vivo.METHODS:Male mice were randomly divided into three groups:groupⅠ(control)mice received the equivalent volumes of phosphate-buffered saline(PBS)intraperitoneally(ip);GroupⅡ[APAP+carboxymethylcellulose(CMC)]mice received 1%CMC(vehicle)2h before APAP injection;GroupⅢ(APAP+CMN)mice received curcumin(10 or 20 mg/kg,ip)2 h before before or after APAP challenge.In GroupsⅡandⅢ,APAP was dissolved in pyrogen-free PBS and injected at a single dose of 300 mg/kg.CMN was dissolved in 1%CMC.Mice were sacrificed 16 h after the APAP injection to determine alanine aminotransferase(ALT)levels in serum and malondialdehyde(MDA)accumulation,superoxide dismutase(SOD)activity and hepatocyte apoptosis in liver tissues.RESULTS:Both pre-and post-treatment with curcumin resulted in a significant decrease in serum ALT compared with APAP treatment group(10 mg/kg:801.46±661.34 U/L;20 mg/kg:99.68±86.48 U/L vs 5406.80±1785.75 U/L,P<0.001,respectively).The incidence of liver necrosis was significantly lowered in CMN treated animals.MDA contents were significantly reduced in 20 mg/kg CMN pretreatment group,but increased in APAP treated group(10.96±0.87 nmol/mg protein vs 16.03±2.58 nmol/mg protein,P<0.05).The decrease of SOD activity in APAP treatment group and the increase of SOD in 20 mg/kg CMN pretreatment group were also detected(24.54±4.95 U/mg protein vs 50.21±1.93 U/mg protein,P<0.05).Furthermore,CMN treatment efficiently protected against APAPinduced apoptosis via increasing Bcl-2/Bax ratio.CONCLUSION:CMN has significant therapeutic potential in both APAP-induced hepatotoxicity and other types of liver diseases.展开更多
AIM To establish a reversible porcine model of acute liver failure(ALF) and treat it with an artificial liver system. METHODS Sixteen pigs weighing 30-35 kg were chosen and administered with acetaminophen(APAP) to ind...AIM To establish a reversible porcine model of acute liver failure(ALF) and treat it with an artificial liver system. METHODS Sixteen pigs weighing 30-35 kg were chosen and administered with acetaminophen(APAP) to induce ALF. ALF pigs were then randomly assigned to either an experimental group(n = 11), in which a treatment procedure was performed, or a control group(n = 5). Treatment was started 20 h after APAP administration and continued for 8 h. Clinical manifestations of all animals, including liver and kidney functions, serum biochemical parameters and survival times were analyzed. RESULTS Twenty hours after APAP administration, the levels of serum aspartate aminotransferase, total bilirubin, creatinine and ammonia were significantly increased, while albumin levels were decreased(P < 0.05). Prothrombin time was found to be extended with progression of ALF. After continuous treatment for 8 h(at 28 h), aspartate aminotransferase, total bilirubin, creatinine, and ammonia showed a decrease in comparison with the control group(P < 0.05). A cross-section of livers revealed signs of vacuolar degeneration, nuclear fragmentation and dissolution.Concerning survival, porcine models in the treatment group survived for longer times with artificial liver system treatment(P < 0.05). CONCLUSION This model is reproducible and allows for quantitative evaluation of new liver systems, such as a bioartificial liver. The artificial liver system(ZHj-3) is safe and effective for the APAP-induced porcine ALF model.展开更多
Many plant-derived natural products have the potential to be hepatoprotective and therefore can be used to treat acute and chronic liver diseases. The challenge is to identify the most promising compounds and evaluate...Many plant-derived natural products have the potential to be hepatoprotective and therefore can be used to treat acute and chronic liver diseases. The challenge is to identify the most promising compounds and evaluate their protective mechanism. In a recently published article, Wang et al evaluated extracts of the plant Gentiana manshurica Kitagawa (GM) in a model of acetaminophen hepatotoxicity. The authors concluded that GM is hepatoprotective against acetaminopheninduced liver injury due to its antioxidant properties and anti-apoptotic capacity. We would like to discuss the limitations of this experimental approach and question the conclusion based on the data presented in this manuscript and the published literature.展开更多
Objective:To investigate the protective effects of Nigella sativa seed extract(NSSE) against acetaminophen(APAP)-induced hepaloloxicity in TIB-73 cells and rats.Methods:Toxicity in TIB-73 cells was induced with 10 μm...Objective:To investigate the protective effects of Nigella sativa seed extract(NSSE) against acetaminophen(APAP)-induced hepaloloxicity in TIB-73 cells and rats.Methods:Toxicity in TIB-73 cells was induced with 10 μmol/L APAP and the protective effects of NSSE were evaluated at 25.50.75,100 μg/mL.For in rim examination,a total of 30 rals were equally divided into five experimental groups:normal control(vehicle),APAP(800 mg/kg body weight single IP injection) as a hepatotoxic control,and three APAP and NS pretreated(2 weeks) groups(APAP+NSSE 100 mg:APAP+NSSE 300 mg and APAP+NSSK 900 mg/kg).Results:TIB-73 cell viability was drastically decreased by(49.0±l.9)%after the 10 μmol/L APAP treatment,which also increased reactive oxygen species production.Co-treatment with NSSE at 25.50.75,and 100 μg/mL significantly improved cell viability and suppressed reactive oxygen species generation.In viro the APAP induced alterations in blood lactate levels,pH,anionic gap,and ion levels(HCO_3^-,Mg^(2+) and K^+),which tended to normalize with the NSSE pretreatment.The NSSE also significantly decreased elevated serum levels of alanine aminotransferase,aspartate aminotransferase,lactate dehydrogenase,and alkaline phosphatase induced by APAP,which correlated with decreased levels of hepatic lipid peroxidation(nialondialdehyde),increased superoxide dismutase levels,and reduced glutathione concentrations.Improved hepatic histology was also found in the treatment groups other than APAP group.Conclusions:The in vitro and in vim findings of this study demonstrated that the NSSE has protective effects against APAP-induced hepalotoxicity and metabolic disturbances by improving antioxidant activities and suppressing both lipid peroxidation and ROS generation.展开更多
AIM:To examine the effects of 2,4-dihydroxybenzophenone(BP-1),a benzophenone derivative used as an ultraviolet light absorbent,on acetaminophen(APAP)induced hepatotoxicity in C57BL/6J mice.METHODS:Mice were administer...AIM:To examine the effects of 2,4-dihydroxybenzophenone(BP-1),a benzophenone derivative used as an ultraviolet light absorbent,on acetaminophen(APAP)induced hepatotoxicity in C57BL/6J mice.METHODS:Mice were administered orally with BP-1 at doses of 200,400 and 800 mg/kg body weight respectively every morning for 4 d before a hepatotoxic dose of APAP(350 mg/kg body weight) was given subcutaneously.Twenty four hours after APAP intoxication,the serum enzyme including serum alaine aminotransferase(ALT),aspartate aminotransferase(AST),lactate dehydrogenase(LDH) were measured and liver histopathologic changes were examined.RESULTS:BP-1 administration dramatically reduced serum ALT,AST and LDH levels.Liver histopathological examination showed that BP-1 administration antagonized APAP-induced liver pathological damage in a dose-dependent manner.Further tests showed that APAP-induced hepatic lipid peroxidation was reduced significantly by BP-1 pretreatment,and glutathione depletion was ameliorated obviously.CONCLUSION:BP-1 can effectively protect C57BL/6J mice from APAP-induced hepatotoxicity,and reduction of oxidative stress might be part of the protection mechanism.展开更多
Acute pancreatitis is rarely associated with drugs. Acetaminophen overdose is a well-known cause of hepatic toxicity, but drug-induced pancreatitis is rarely reported, especially after mild overdose. A 32-yearold woma...Acute pancreatitis is rarely associated with drugs. Acetaminophen overdose is a well-known cause of hepatic toxicity, but drug-induced pancreatitis is rarely reported, especially after mild overdose. A 32-yearold woman presented with nausea and vomiting for 12 h, but no abdominal pain following an overdose of eight Tylenol tablets containing acetaminophen(325 mg acetaminophen per tablet). Laboratory results on admission showed abnormal amylase and lipase levels but completely normal liver function. Magnetic resonance cholangiopancreatography revealed mild swelling of the pancreas without fluid collection around the pancreas. The patient complained of severe abdominal pain five days after admission when attempting to drink water and liquids. Eight days after admission, fluid around the pancreas was observed by computed tomography. The patient was subsequently diagnosed with acetaminophen-induced acute pancreatitis after exclusion of common causes. Routine treatment for pancreatitis and N-acetylcysteine were administered to prevent disease progression. The patient was discharged in good condition.展开更多
A simple and rapid liquid chromatography-tandem mass spectrometry （LC-MS/MS） method was de- veloped and validated for simultaneous determination of acetaminophen and oxycodone in human plasma. Acetaminophen-d4 and o...A simple and rapid liquid chromatography-tandem mass spectrometry （LC-MS/MS） method was de- veloped and validated for simultaneous determination of acetaminophen and oxycodone in human plasma. Acetaminophen-d4 and oxycodone-d3 were used as internal standards. The challenge en- countered in the method development that the high plasma concentration level of acetaminophen made the MS response saturated while the desired lower limit of quantification （LLOQ,） for oxycodone was hard to reach was well solved. The analytes were extracted by protein precipitation using acetonitrile. The matrix effect of the analytes was avoided by chromatographic separation using a hydrophilic C18 column coupled with gradient elution. Multiple reaction monitoring in positive ion mode was performed on tandem mass spectrometer employing electrospray ion source. The calibration curves were linear over the concentration ranges of 40.0-8000 ng/mL and 0.200-40.0 ng/mL for acetaminophen and oxycodone, respectively. This method, which could contribute to high throughput analysis and better clinical drug monitoring, was successfully applied to a pharmacokinetic study in healthy Chinese volunteers.展开更多
基金supported by the National Key R&D Program of China(2023YFB3507004)National Natural Science Foundation of China(U21A20148)+5 种基金International Partnership Program of Chinese Academy of Sciences(116134KYSB20210052)Anhui Provincial Natural Science Foundation(2308085QE183,2308085QE181)CASHIPS Director’s Fund(YZJJ2024QN44,YZJJ2023QN43)Heye Health Technology Chong Ming Project(HYCMP2021010)China Post-doctoral Science Foundation(2023M743536)Science Research Fund for Postdoctoral in Anhui Province(2023B669)。
文摘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.
文摘OBJECTIVE Acetaminophen(APAP),also known as paracetamol,is a commonly used antipyretic,anal⁃gesic and anti-inflammatory drug.However,during the use of APAP for more than half a century,people have not only used APAP to fight diseases but have also suffered the adverse effects brought about by APAP for more than half a cen⁃tury.The most serious adverse reaction to APAP is hepatotoxicity caused by overdose or long-term use.In Chinese tra⁃ditional medicine,chrysanthemums have the functions of dispelling wind,dissipating heat,clearing the liver and improv⁃ing eyesight.Although the chrysanthemum variety named Bianliang ziyu from Kaifeng is not a medicinal variety,it has good value for medicine and food.The aim of this study was to investigate the protective effect of Bianliang Ziyu extract(BZE)on APAP-damaged rats and the potential molecular mechanism.METHODS Male Sprague-Dawley rats(200-220 g)were intragastrically administered BZE(110,220 and 440 mg·kg^-1)for 8 d.On the ninth day,APAP(800 mg·kg^-1)was administered intragastrically to the rats 0.5 h after BZE administration to induced drug-induced liver injury.The serum and liver samples were collected after 24 h.The levels of alanine aminotransferase(ALT),aspartic aminotransferase(AST),reactive oxygen species(ROS),malondialdehyde(MDA),superoxide dismutase(SOD)and glutathione(GSH)in serum and liver tissue of rats were detected by kit method.HE staining was used to observe the histopathological changes in the liver of rat.The effects of BZE on the expression of the oxidative stress related proteins and the mitochondrial biosyn⁃thesis related proteins were detected by Western blot.RESULTS The results showed that BZE significantly reduced the levels of ALT,AST,MDA and ROS and increased the levels of GSH and SOD caused by APAP.Moreover,BZE increased phosphorylation of AMP-activated protein kinase(AMPK)and glycogen synthase kinase 3β(GSK3β),promoted the nuclear translocation of nuclear factor-erythroid 2-related factor 2(Nrf2).BZE also upregulated the expression of mitochondrial biosynthesis related proteins such as peroxisome proliferator-activated receptorγ(PPAR-γ),peroxisome proliferator-activated receptorγcoactivator-1α(PGC-1α),mitochondrial transcription factor(TFAM)and nuclear respira⁃tory factor 1(NRF1).CONCLUSION BZE alleviates APAP-induced liver injury in rats by inhibiting oxidative stress via GSK3β-Nrf2 signaling and the mitochondrial biosynthesis pathway mediated by AMPK.
文摘AIM To evaluate the safety and efficacy of the bioartificial liver support system in canines with acute liver failure (ALF). METHODS Nine canines with acute liver failure by acetaminophen induced received TECA Ⅰ bioartificial liver support system (BALSS) from Hong Kong TECA LTD Co. Blood was perfused through a hollow fiber tube containing (1 2)×10 10 the porcine hepatocytes. In contrast, another 10 canines with acute liver failure by Acetaminophen received drugs. Each treatment lasted 6 hours. RESULTS BALSS treatment resulted in beneficial effects for acetaminophen induced ALF canines with survival and with the recovery of the liver functions and tissues, and plasma ammonia decreased from 135 9μmol/L ± 17 5μmol/L to 65 7μmol/L ± 22 0μmol/L , 32 5μmol/L ± 8 8μmol/L , GPT from 97 8U/L ± 8 7U/L to 64 8U/L ± 11 9U/L , 19 0U/L ± 6 3U/L , GOT from 103 0U/L ± 16 7U/L to 75 7U/L ± 19 6U/L , 26 5U/L ± 5 0U/L , and AKP from 158 3U/L ± 12 1U/L to 114 5U/L ± 19 8U/L , 43 8U/L ± 5 6U/L during and after the treatment. In contrast, 10 ALF canines in both the drug and control groups died 1 or 2 days after treatment. CONCLUSION TECA 1 artificial liver support system is safe and efficacious for canines with acute liver failure.
文摘AIM: To explore the mechanism of protection against acetaminophen-induced acute liver injury by Liuweiwuling tablets.METHODS: Intraperitoneal injections of acetaminophen(250 mg/kg) were used to induce acute liver injury in male C57BL/6 mice.A total of 24 healthy mice were randomly assigned to two groups: an acute liver injury group(control group) and a Liuweiwuling tablet group.Mice were given Liuweiwuling tablets or a vehicle(PBS) orally prior to the administration of acetaminophen.Serum alanine aminotransferase(ALT) and aspartate aminotransaminase(AST) levels were measured at different time points within one week,and pathological examinations of liver tissues were performed 36 h after induction of acute liver injury.Serum inflammatory cytokines,such as high mobility group box protein B1(HMGB1),tumor necrosis factor(TNF)-α and interleukin IL-1b,were detected using an ELISA method according to the manufacturer's instructions.Hepatic morphological changes at 36 h were assessed by hematoxylin and eosin staining.Expression of proliferating cell nuclear antigen(PCNA) in liver tissue was determined by Western blot analysis.The m RNA levels of hepatocyte proliferation markers(PCNA,Cyclin D1 and p21) were detected by real-time quantitative reverse transcription-polymerase chain reaction.RESULTS: The levels of ALT/AST in the Liuweiwuling tablet group were decreased significantly at 6,12 and 24 h compared to that of the control group(654.38 ± 120.87 vs 1566.17 ± 421.64,1154.18 ± 477.72 vs 4654.84 ± 913.71 and 935.13 ± 252.34 vs 4553.75 ± 727.37,P < 0.01).Serum HMGB1 levels at 6 and 12 h for the Liuweiwuling tablet group were significantly lower than those of the control group(23.49 ± 3.89 vs58.6 ± 3.65,61.62 ± 13.07 vs 27.32 ± 5.97,P < 0.01).Furthermore,serum TNF-α and IL-1b levels at 12 h in the Liuweiwuling tablet group were also significantly lower than those of the control group(299.35 ± 50.61 vs 439.03 ± 63.59,57.42 ± 12.98 vs 160.07 ± 49.87,P < 0.01).Centrilobular necrosis was evident in liver tissue of mice with acetaminophen-induced acute liver injury,but was almost abolished in the Liuweiwuling tablet group.The expression levels of PCNA and Cyclin D1 were up-regulated in liver tissue in the Liuweiwuling tablet group(321.08 ± 32.87 vs 157.91 ± 21.52,196.37 ± 25.39 vs 68.72 ± 11.27,P < 0.01); however,expression of p21 in liver tissue was downregulated compared to that of the control group(40.26 ± 9.97 vs 138.24 ± 13.66,P < 0.01).CONCLUSION: Liuweiwuling tablets can attenuate acute liver injury by decreasing inflammatory cytokine(HMGB1,TNF-α and IL-1b) levels and promoting liver regeneration.
文摘Objective:To investigate and compare the hepatoprotective effects of crude ethanolic and aqueous extracts of Phyllanthus acidus（L.） Skeels（P.acidus） leaves on acetaminophen（APAP） and thioacetamide（TAA） induced liver toxicity in wistar rats.Silymarin was the reference hepatoprotective agent.Methods:In two different sets of experiments,the P.acidus extracts （200 and 400 mg/kg,body weight） and silymarin（100 mg/kg,body weight） were given orally for 7 days and a single dose of APAP（2 g/kg,per oral） or TAA（100 mg/kg,subcutaneous） were given to rats.The level of serum aspartate transaminase（AST）,alanine transaminase（ALT）,alkaline phosphatase（ALP）,total bilirubin and total protein were monitored to assess hepatotoxicity and hepatoprotection.Results:APAP or TAA administration caused severe hepatic damage in rats as evident from significant rise in serum AST,ALT,ALP,total bilirubin and concurrent depletion in total serum protein.The P.acidus extracts and silymarin prevented the toxic effects of APAP or TAA on the above serum parameters indicating the hepatoprotective action.The aqueous extract was found to be more potent than the corresponding ethanolic extract against both toxicants.The phenolic and flavonoid content（175.02±4.35 and 74.68±1.28,respectively） and 2,2-diphenyl-1- picrylhydrazil（DPPH）[IC<sub>50</sub>=（33.2±0.31）μg/mL]scavenging potential was found maximum with aqueous extract as compared to ethanolic extract.Conclusions:The results of present study suggests that the aqueous extract of P.acidus leaves has significant hepatoprotective activity on APAP and TAA induced hepatotoxicity,which might be associate with its high phenolic and flavonoid content and antioxidant properties.
基金Supported by National Natural Science Foundation of China,No.81271872Health Department of Hubei Province,No.XF2012-5Jingzhou Bureau of Science and Technology
文摘AIM:To explore the effects of curcumin(CMN)on hepatic injury induced by acetaminophen(APAP)in vivo.METHODS:Male mice were randomly divided into three groups:groupⅠ(control)mice received the equivalent volumes of phosphate-buffered saline(PBS)intraperitoneally(ip);GroupⅡ[APAP+carboxymethylcellulose(CMC)]mice received 1%CMC(vehicle)2h before APAP injection;GroupⅢ(APAP+CMN)mice received curcumin(10 or 20 mg/kg,ip)2 h before before or after APAP challenge.In GroupsⅡandⅢ,APAP was dissolved in pyrogen-free PBS and injected at a single dose of 300 mg/kg.CMN was dissolved in 1%CMC.Mice were sacrificed 16 h after the APAP injection to determine alanine aminotransferase(ALT)levels in serum and malondialdehyde(MDA)accumulation,superoxide dismutase(SOD)activity and hepatocyte apoptosis in liver tissues.RESULTS:Both pre-and post-treatment with curcumin resulted in a significant decrease in serum ALT compared with APAP treatment group(10 mg/kg:801.46±661.34 U/L;20 mg/kg:99.68±86.48 U/L vs 5406.80±1785.75 U/L,P<0.001,respectively).The incidence of liver necrosis was significantly lowered in CMN treated animals.MDA contents were significantly reduced in 20 mg/kg CMN pretreatment group,but increased in APAP treated group(10.96±0.87 nmol/mg protein vs 16.03±2.58 nmol/mg protein,P<0.05).The decrease of SOD activity in APAP treatment group and the increase of SOD in 20 mg/kg CMN pretreatment group were also detected(24.54±4.95 U/mg protein vs 50.21±1.93 U/mg protein,P<0.05).Furthermore,CMN treatment efficiently protected against APAPinduced apoptosis via increasing Bcl-2/Bax ratio.CONCLUSION:CMN has significant therapeutic potential in both APAP-induced hepatotoxicity and other types of liver diseases.
文摘AIM To establish a reversible porcine model of acute liver failure(ALF) and treat it with an artificial liver system. METHODS Sixteen pigs weighing 30-35 kg were chosen and administered with acetaminophen(APAP) to induce ALF. ALF pigs were then randomly assigned to either an experimental group(n = 11), in which a treatment procedure was performed, or a control group(n = 5). Treatment was started 20 h after APAP administration and continued for 8 h. Clinical manifestations of all animals, including liver and kidney functions, serum biochemical parameters and survival times were analyzed. RESULTS Twenty hours after APAP administration, the levels of serum aspartate aminotransferase, total bilirubin, creatinine and ammonia were significantly increased, while albumin levels were decreased(P < 0.05). Prothrombin time was found to be extended with progression of ALF. After continuous treatment for 8 h(at 28 h), aspartate aminotransferase, total bilirubin, creatinine, and ammonia showed a decrease in comparison with the control group(P < 0.05). A cross-section of livers revealed signs of vacuolar degeneration, nuclear fragmentation and dissolution.Concerning survival, porcine models in the treatment group survived for longer times with artificial liver system treatment(P < 0.05). CONCLUSION This model is reproducible and allows for quantitative evaluation of new liver systems, such as a bioartificial liver. The artificial liver system(ZHj-3) is safe and effective for the APAP-induced porcine ALF model.
文摘Many plant-derived natural products have the potential to be hepatoprotective and therefore can be used to treat acute and chronic liver diseases. The challenge is to identify the most promising compounds and evaluate their protective mechanism. In a recently published article, Wang et al evaluated extracts of the plant Gentiana manshurica Kitagawa (GM) in a model of acetaminophen hepatotoxicity. The authors concluded that GM is hepatoprotective against acetaminopheninduced liver injury due to its antioxidant properties and anti-apoptotic capacity. We would like to discuss the limitations of this experimental approach and question the conclusion based on the data presented in this manuscript and the published literature.
基金supported in part by the Brain Korea 21 Plus program of the National Research Foundation of Korea Grant
文摘Objective:To investigate the protective effects of Nigella sativa seed extract(NSSE) against acetaminophen(APAP)-induced hepaloloxicity in TIB-73 cells and rats.Methods:Toxicity in TIB-73 cells was induced with 10 μmol/L APAP and the protective effects of NSSE were evaluated at 25.50.75,100 μg/mL.For in rim examination,a total of 30 rals were equally divided into five experimental groups:normal control(vehicle),APAP(800 mg/kg body weight single IP injection) as a hepatotoxic control,and three APAP and NS pretreated(2 weeks) groups(APAP+NSSE 100 mg:APAP+NSSE 300 mg and APAP+NSSK 900 mg/kg).Results:TIB-73 cell viability was drastically decreased by(49.0±l.9)%after the 10 μmol/L APAP treatment,which also increased reactive oxygen species production.Co-treatment with NSSE at 25.50.75,and 100 μg/mL significantly improved cell viability and suppressed reactive oxygen species generation.In viro the APAP induced alterations in blood lactate levels,pH,anionic gap,and ion levels(HCO_3^-,Mg^(2+) and K^+),which tended to normalize with the NSSE pretreatment.The NSSE also significantly decreased elevated serum levels of alanine aminotransferase,aspartate aminotransferase,lactate dehydrogenase,and alkaline phosphatase induced by APAP,which correlated with decreased levels of hepatic lipid peroxidation(nialondialdehyde),increased superoxide dismutase levels,and reduced glutathione concentrations.Improved hepatic histology was also found in the treatment groups other than APAP group.Conclusions:The in vitro and in vim findings of this study demonstrated that the NSSE has protective effects against APAP-induced hepalotoxicity and metabolic disturbances by improving antioxidant activities and suppressing both lipid peroxidation and ROS generation.
基金Supported by Drug Innovation Program of National Science and Technology Project, No. 2009ZX09103-007
文摘AIM:To examine the effects of 2,4-dihydroxybenzophenone(BP-1),a benzophenone derivative used as an ultraviolet light absorbent,on acetaminophen(APAP)induced hepatotoxicity in C57BL/6J mice.METHODS:Mice were administered orally with BP-1 at doses of 200,400 and 800 mg/kg body weight respectively every morning for 4 d before a hepatotoxic dose of APAP(350 mg/kg body weight) was given subcutaneously.Twenty four hours after APAP intoxication,the serum enzyme including serum alaine aminotransferase(ALT),aspartate aminotransferase(AST),lactate dehydrogenase(LDH) were measured and liver histopathologic changes were examined.RESULTS:BP-1 administration dramatically reduced serum ALT,AST and LDH levels.Liver histopathological examination showed that BP-1 administration antagonized APAP-induced liver pathological damage in a dose-dependent manner.Further tests showed that APAP-induced hepatic lipid peroxidation was reduced significantly by BP-1 pretreatment,and glutathione depletion was ameliorated obviously.CONCLUSION:BP-1 can effectively protect C57BL/6J mice from APAP-induced hepatotoxicity,and reduction of oxidative stress might be part of the protection mechanism.
文摘Acute pancreatitis is rarely associated with drugs. Acetaminophen overdose is a well-known cause of hepatic toxicity, but drug-induced pancreatitis is rarely reported, especially after mild overdose. A 32-yearold woman presented with nausea and vomiting for 12 h, but no abdominal pain following an overdose of eight Tylenol tablets containing acetaminophen(325 mg acetaminophen per tablet). Laboratory results on admission showed abnormal amylase and lipase levels but completely normal liver function. Magnetic resonance cholangiopancreatography revealed mild swelling of the pancreas without fluid collection around the pancreas. The patient complained of severe abdominal pain five days after admission when attempting to drink water and liquids. Eight days after admission, fluid around the pancreas was observed by computed tomography. The patient was subsequently diagnosed with acetaminophen-induced acute pancreatitis after exclusion of common causes. Routine treatment for pancreatitis and N-acetylcysteine were administered to prevent disease progression. The patient was discharged in good condition.
文摘A simple and rapid liquid chromatography-tandem mass spectrometry （LC-MS/MS） method was de- veloped and validated for simultaneous determination of acetaminophen and oxycodone in human plasma. Acetaminophen-d4 and oxycodone-d3 were used as internal standards. The challenge en- countered in the method development that the high plasma concentration level of acetaminophen made the MS response saturated while the desired lower limit of quantification （LLOQ,） for oxycodone was hard to reach was well solved. The analytes were extracted by protein precipitation using acetonitrile. The matrix effect of the analytes was avoided by chromatographic separation using a hydrophilic C18 column coupled with gradient elution. Multiple reaction monitoring in positive ion mode was performed on tandem mass spectrometer employing electrospray ion source. The calibration curves were linear over the concentration ranges of 40.0-8000 ng/mL and 0.200-40.0 ng/mL for acetaminophen and oxycodone, respectively. This method, which could contribute to high throughput analysis and better clinical drug monitoring, was successfully applied to a pharmacokinetic study in healthy Chinese volunteers.
