Due to the endocrine toxicity,neurotoxic,and reproductive toxicity to organisms,the sources and risks of brominated organic pollutants have attracted widespread attention.However,knowledge gaps remain in the brominati...Due to the endocrine toxicity,neurotoxic,and reproductive toxicity to organisms,the sources and risks of brominated organic pollutants have attracted widespread attention.However,knowledge gaps remain in the bromination processes of emerging phenolic pollutants in plants,whichmay increase the potential health risk associated with food exposure.Our study discovered that light induced generation and accumulation of more toxic brominated organic compounds(Br-org)in lettuce leaves under the stress of acetaminophen(ACE)than that without light,as evidenced by an increase in C-Br bond intensity in FTIR analysis.This result can be explained by the oxidation of bromide ions(Br^(-))by reactive species(ROS and ^(3)Chl*)of chloroplast into reactive bromine species(RBS).The main mechanism is that the redox of Br^(-)reduced the oxidative damage of ACE to the structure and function of chloroplasts,providing good conditions for light energy uptake and utilization and promoting the increase of pigments and active species.Compared with the dark group exposed to 5 mg/L Br^(-),the pigment content,H_(2)O_(2) and ^(1)O_(2) level of the light group increased by 56%,84% and 69%,respectively.On the other hand,RBS attacks certain electrophilic organic compounds in leaves to generate Br^(-)org.Triple excited state of chlorophyll(^(3)Chl^(*))was the dominant species for the transformation of ACE,while RBS is a key factor in the generation of Br-org in the Br^(-)/light/chlorophyll system.A total of six transformation products were identified by HPLC-MS/MS,which were involved in three transformation pathways:methylation,hydroxyl oxidation and hydroxylation followed by bromination.This is the first report that Br^(-)could enter the chloroplast and improved chloroplast structure under ACE stress,and elucidated the bromination mechanism of organics in terrestrial plant involving of biophotochemical bromination in chloroplast besides enzyme-catalyzed bromination.This study is beneficial for risk assessment and prevention of emerging phenolic pollutants.展开更多
Objective:To assess the effects of turmeric extract and its compounds on oxidative stress,inflammation,and apoptosis in acetaminophen-induced liver injury.Methods:HepG2 cells were administered with acetaminophen(40 mM...Objective:To assess the effects of turmeric extract and its compounds on oxidative stress,inflammation,and apoptosis in acetaminophen-induced liver injury.Methods:HepG2 cells were administered with acetaminophen(40 mM)to induce hepatotoxicity,followed by treatment with turmeric extract and its isolated compounds including curcumin,demethoxycurcumin,bis-demethoxycurcumin and ar-turmerone at 5,25,and 125μg/mL.IL-1β,IL-6,and IL-10 levels were quantified with ELISA kits.Further,qRT-PCR was used to analyze the mRNA expression of JNK,Casp-9,and Casp-3.Meanwhile,the levels of nitric oxide and lactate dehydrogenase were analyzed using colorimetric assay.Results:Acetaminophen administration caused an increase in the levels of lactate dehydrogenase,nitric oxide,IL-1β,IL-6,and the mRNA expression of JNK,Casp-9,and Casp-3 in HepG2 cells while reducing IL-10 levels.Treatment with turmeric extract,curcumin,demethoxycurcumin,bis-demethoxycurcumin,and ar-turmerone lowered IL-1β,IL-6,nitric oxide,and lactate dehydrogenase levels,downregulated the mRNA expression of JNK,Casp-9,and Casp-3,and increased IL-10 levels.Conclusions:Turmeric extract and its compounds have significant hepatoprotective activity and could be further explored for the treatment of liver damage.展开更多
Acetaminophen(APAP)used as an antipyretic and analgesic agent can cause acute liver injury(AILI)under overdose.Sanghuangporous vaninii is an edible fungus with abundant metabolites exhibits excellent hepatoprotective ...Acetaminophen(APAP)used as an antipyretic and analgesic agent can cause acute liver injury(AILI)under overdose.Sanghuangporous vaninii is an edible fungus with abundant metabolites exhibits excellent hepatoprotective activities,but the effect for AILI is not yet fully understood.In this study,the polyphenol rich extract from S.vaninii(PSV)was prepared,with a total phenolic content of 75.72%and 34 compounds.The data of hepatoprotection indicated that PSV obviously alleviated the hepatocellular injury induced by APAP in vivo and in vitro.The protective mechanism of PSV against APAP-induced AILI might be attributed to the activating NRF2/GPX4 pathway.Based on network pharmacology analysis,the active components of PSV such as caffeic acid,osmundacetone and hispolone played a key role in hepatoprotection of PSV.Consequently,this study highlights the protection of PSV on AILI,which provides new insight into bioactivities of S.vaninii.展开更多
BACKGROUND In the management of postoperative pain following total joint arthroplasty(TJA),the use of nonsteroidal anti-inflammatory drugs,including acetaminophen,plays a key role in alleviating pain.However,the compa...BACKGROUND In the management of postoperative pain following total joint arthroplasty(TJA),the use of nonsteroidal anti-inflammatory drugs,including acetaminophen,plays a key role in alleviating pain.However,the comparison between intravenous and oral acetaminophen administration in patients undergoing full joint replacement surgery remains controversial.AIM To assess the effectiveness of intravenous and oral acetaminophen in alleviating pain and supporting rehabilitation following TJA.METHODS PubMed,Embase and the Cochrane Library were comprehensively searched to identify cohort studies.The effects of intravenous and oral acetaminophen for managing pain and supporting rehabilitation following TJA were analysed using randomized controlled trials.PRISMA guidelines were followed.The effectiveness of the administration routes was compared based on visual analogue scale(VAS)scores at 24 and 48 h,total morphine usage within 24 h,and total duration of hospital stay.RESULTS The meta-analysis included seven studies comparing intravenous acetaminophen groups and oral acetaminophen groups.The results demonstrated that oral acetaminophen was comparable to intravenous acetaminophen with regard to VAS scores at 24 h and 48 h(P=0.76 and 0.08,respectively).The difference in total morphine use between the two groups was not significant(P=0.22).However,the total hospital stay duration of the intravenous acetaminophen groups was significantly reduced compared to the oral acetaminophen groups(P=0.0005),showing significant advantages in optimizing postoperative recovery and shortening hospitalisation time.CONCLUSION After TJA surgery,intravenous injection of acetaminophen can shorten hospitalisation time and is suitable for rapid analgesia,Oral administration has become the preferred choice for mild cases due to its convenience and economy,providing a basis for clinical drug selection.展开更多
Background:Drug-induced liver injury is happening more often,and acetaminophen-induced liver injury is the main cause of drug-induced liver injury.We found that the protective effect of cucurbitacin B(CuB)in acetamino...Background:Drug-induced liver injury is happening more often,and acetaminophen-induced liver injury is the main cause of drug-induced liver injury.We found that the protective effect of cucurbitacin B(CuB)in acetaminophen-induced liver injury is still unclear.Therefore,we constructed an in vitro model of acute liver injury using BRL-3A cells to explore the possible therapeutic impact and mechanism of CuB.Methods:In this study,cell viability assay,reactive oxygen species assay,immunofluorescence assay,RT-qPCR,and Western blot were used to investigate the therapeutic effect and mechanism of CuB on BRL-3A cells injured by acetaminophen.Results:In the present study,CuB could significantly improve the viability of BRL-3A cells,reduce intracellular lipid reactive oxygen species,aspartate aminotransferase,alanine aminotransferase,and malondialdehyde,and increase the intracellular glutathione and mitochondrial membrane potential.CuB significantly increased the protein levels of intracellular transporters cystine/glutamate transporter Xct(SLC7A11)and glutathione peroxidase 4(GPX4).Further investigation of the mechanism showed that CuB inhibited lipid peroxidation by activating nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation and upregulating heme oxygenase 1(HO-1)and NAD(P)H quinone oxidoreductase 1(NQO1).Conclusion:CuB reduces acute liver damage caused by acetaminophen via the Nrf2 pathway.展开更多
BACKGROUND High levels of acetaminophen(APAP)consumption can result in significant liver toxicity.Mogroside V(MV)is a bioactive,plant-derived triterpenoid known for its various pharmacological activities.However,the i...BACKGROUND High levels of acetaminophen(APAP)consumption can result in significant liver toxicity.Mogroside V(MV)is a bioactive,plant-derived triterpenoid known for its various pharmacological activities.However,the impact of MV on acute liver injury(ALI)is unknown.AIM To investigate the hepatoprotective potential of MV against liver damage caused by APAP and to examine the underlying mechanisms.METHODS Mice were divided into three groups:Saline,APAP and APAP+MV.MV(10 mg/kg)was given intraperitoneally one hour before APAP(300 mg/kg)administration.Twenty-four hours after APAP exposure,serum transaminase levels,liver necrotic area,inflammatory responses,nitrotyrosine accumulation,and c-jun-N-terminal kinase(JNK)activation were assessed.Additionally,we analyzed reactive oxygen species(ROS)levels,JNK activation,and cell death in alpha mouse liver 12(AML12)cells.RESULTS MV pre-treatment in vivo led to a reduction in the rise of aspartate transaminase and alanine transaminase levels,mitigated liver damage,decreased nitrotyrosine accumulation,and blocked JNK phosphorylation resulting from APAP exposure,without affecting glutathione production.Similarly,MV diminished the APAP-induced increase in ROS,JNK phosphorylation,and cell death in vitro.CONCLUSION Our study suggests that MV treatment alleviates APAP-induced ALI by reducing ROS and JNK activation.展开更多
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
Acetaminophen,also known as N-acetyl-p-aminophenol(APAP),is commonly used as an antipyretic and analgesic agent.APAP overdose can induce hepatic toxicity,known as acetaminophen-induced liver injury(AILI).However,thera...Acetaminophen,also known as N-acetyl-p-aminophenol(APAP),is commonly used as an antipyretic and analgesic agent.APAP overdose can induce hepatic toxicity,known as acetaminophen-induced liver injury(AILI).However,therapeutic doses of APAP can also induce AILI in patients with excessive alcohol intake or who are fasting.Hence,there is a need to understand the potential pathological mechanisms underlying AILI.In this review,we summarize three main mechanisms involved in the pathogenesis of AILI:hepatocyte necrosis,sterile inflammation,and hepatocyte regeneration.The relevant factors are elucidated and discussed.For instance,N-acetyl-p-benzoquinone imine(NAPQI)protein adducts trigger mitochondrial oxidative/nitrosative stress during hepatocyte necrosis,danger-associated molecular patterns(DAMPs)are released to elicit sterile inflammation,and certain growth factors contribute to liver regeneration.Finally,we describe the current potential treatment options for AILI patients and promising novel strategies available to researchers and pharmacists.This review provides a clearer understanding of AILI-related mechanisms to guide drug screening and selection for the clinical treatment of AILI patients in the future.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
We investigated the potential hepatoprotective effect of Radix Bupleuri(RB) by inducing acute liver injury(ALI) in an animal model using acetaminophen(APAP) after pretreatment with RB aqueous extract for three consecu...We investigated the potential hepatoprotective effect of Radix Bupleuri(RB) by inducing acute liver injury(ALI) in an animal model using acetaminophen(APAP) after pretreatment with RB aqueous extract for three consecutive days. Compared to those of the APAP group, the biochemical and histological results of the RB pretreatment group showed lower serum aspartate transaminase(AST) and alanine transaminase(ALT) levels as well as less liver damage. Pharmacokinetic study of the toxicity related marker acetaminophen-cysteine(APC) revealed a lower exposure level in rats, suggesting that RB alleviated APAP-induced liver damage by preventing glutathione(GSH) depletion. The results of cocktail approach showed significant inhibition of CYP2 E1 and CYP3 A activity. Further investigation revealed the increasing of CYP2 E1 and CYP3 A protein was significantly inhibited in pretreatment group,while no obvious effect on gene expression was found. Therefore, this study clearly demonstrates that RB exhibited significant protective action against APAP-induced acute live injury via pretreatment, and which is partly through inhibiting the increase of activity and translation of cytochrome P450 enzymes, rather than gene transcription.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
Commercial available zero valent aluminum under air-equilibrated acidic conditions（ZVAl/H＋/air system） demonstrated an excellent capacity to remove aqueous organic compounds.Acetaminophen（ACTM）,the active ingredi...Commercial available zero valent aluminum under air-equilibrated acidic conditions（ZVAl/H＋/air system） demonstrated an excellent capacity to remove aqueous organic compounds.Acetaminophen（ACTM）,the active ingredient of the over-the-counter drug Tylenol？,is widely present in the aquatic environment and therefore the treatment of ACTM-contaminated water calls for further research.Herein we investigated the oxidative removal of ACTM by ZVAl/H＋/air system and the reaction mechanism.In acidic solutions（pH 3.5）,ZVAl displayed an excellent capacity to remove ACTM.More than 99% of ACTM was eliminated within 16 hr in pH 1.5 reaction solutions initially containing 2.0 g/L aluminum and 2.0 mg/L ACTM at 25 ± 1℃.Higher temperature and lower pH facilitated ACTM removal.The addition of different iron species Fe0,Fe2＋ and Fe3＋ into ZVAl/H＋/air system dramatically accelerated the reaction likely due to the enhancing transformation of H2O2 to HO.via Fenton＇s reaction.Furthermore,the primary intermediate hydroquinone and the anions formate,acetate and nitrate,were identified and a possible reaction scheme was proposed.This work suggested that ZVAl/H＋/air system may be potentially employed to treat ACTM-contaminated water.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
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 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
Chlorogenic acid（CGA）, a polyphenolic compound, is abundant in fruits, dietary vegetables, and some medicinal herbs. This study investigated the prevention of CGA against acetaminophen（AP）-induced hepatotoxicity a...Chlorogenic acid（CGA）, a polyphenolic compound, is abundant in fruits, dietary vegetables, and some medicinal herbs. This study investigated the prevention of CGA against acetaminophen（AP）-induced hepatotoxicity and its engaged mechanisms. CGA reversed the decreased cell viability induced by AP in L-02 cells in vitro. In addition, CGA reduced the AP-induced increased serum levels of alanine/aspartate aminotransferase（ALT/AST） in vivo. The effect of CGA on cytochrome P450（CYP） enzymatic（CYP2E1, CYP1A2, and CYP3A4） activities showed that CGA caused very little inhibition on CYP2E1 and CYP1A2 enzymatic activities, but not CYP3A4. The measurement of liver malondialdehyde（MDA）, reactive oxygen species（ROS）, and glutathione（GSH） levels showed that CGA prevented AP-induced liver oxidative stress injury. Further, CGA increased the AP-induced decreased m RNA expression of peroxiredoxin（Prx） 1, 2, 3, 5, 6, epoxide hydrolase（Ephx） 2, and polymerase（RNA） II（DNA directed） polypeptide K（Polr2k）, and nuclear factor erythroid-2-related factor 2（Nrf2）. In summary, CGA ameliorates the AP-induced liver injury probably by slightly inhibiting CYP2E1 and CYP1A2 enzymatic properties. In addition, cellular important antioxidant signals such as Prx1, 2, 3, 5, 6, Ephx2, Polr2 k, and Nrf2 also contributed to the protection of CGA against AP-induced oxidative stress injury.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
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
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
基金supported by the National Natural Science Foundation of China(Nos.42377428 and 42077391)the National Key Research&Developmental Program of China(No.2022YFC3701301)+1 种基金the Shandong Provincial Natural Science Foundation,China(Nos.ZR2020ZD34 and ZR2023YQ031)the Instrument Improvement Funds of Shandong University Public Technology Platform(No.ts20230108).
文摘Due to the endocrine toxicity,neurotoxic,and reproductive toxicity to organisms,the sources and risks of brominated organic pollutants have attracted widespread attention.However,knowledge gaps remain in the bromination processes of emerging phenolic pollutants in plants,whichmay increase the potential health risk associated with food exposure.Our study discovered that light induced generation and accumulation of more toxic brominated organic compounds(Br-org)in lettuce leaves under the stress of acetaminophen(ACE)than that without light,as evidenced by an increase in C-Br bond intensity in FTIR analysis.This result can be explained by the oxidation of bromide ions(Br^(-))by reactive species(ROS and ^(3)Chl*)of chloroplast into reactive bromine species(RBS).The main mechanism is that the redox of Br^(-)reduced the oxidative damage of ACE to the structure and function of chloroplasts,providing good conditions for light energy uptake and utilization and promoting the increase of pigments and active species.Compared with the dark group exposed to 5 mg/L Br^(-),the pigment content,H_(2)O_(2) and ^(1)O_(2) level of the light group increased by 56%,84% and 69%,respectively.On the other hand,RBS attacks certain electrophilic organic compounds in leaves to generate Br^(-)org.Triple excited state of chlorophyll(^(3)Chl^(*))was the dominant species for the transformation of ACE,while RBS is a key factor in the generation of Br-org in the Br^(-)/light/chlorophyll system.A total of six transformation products were identified by HPLC-MS/MS,which were involved in three transformation pathways:methylation,hydroxyl oxidation and hydroxylation followed by bromination.This is the first report that Br^(-)could enter the chloroplast and improved chloroplast structure under ACE stress,and elucidated the bromination mechanism of organics in terrestrial plant involving of biophotochemical bromination in chloroplast besides enzyme-catalyzed bromination.This study is beneficial for risk assessment and prevention of emerging phenolic pollutants.
基金funded by Maranatha Christian University,Bandung,Indonesia for Productive Lecturer Research under grant number:011/SK/ADD/UKM/IV/2024.
文摘Objective:To assess the effects of turmeric extract and its compounds on oxidative stress,inflammation,and apoptosis in acetaminophen-induced liver injury.Methods:HepG2 cells were administered with acetaminophen(40 mM)to induce hepatotoxicity,followed by treatment with turmeric extract and its isolated compounds including curcumin,demethoxycurcumin,bis-demethoxycurcumin and ar-turmerone at 5,25,and 125μg/mL.IL-1β,IL-6,and IL-10 levels were quantified with ELISA kits.Further,qRT-PCR was used to analyze the mRNA expression of JNK,Casp-9,and Casp-3.Meanwhile,the levels of nitric oxide and lactate dehydrogenase were analyzed using colorimetric assay.Results:Acetaminophen administration caused an increase in the levels of lactate dehydrogenase,nitric oxide,IL-1β,IL-6,and the mRNA expression of JNK,Casp-9,and Casp-3 in HepG2 cells while reducing IL-10 levels.Treatment with turmeric extract,curcumin,demethoxycurcumin,bis-demethoxycurcumin,and ar-turmerone lowered IL-1β,IL-6,nitric oxide,and lactate dehydrogenase levels,downregulated the mRNA expression of JNK,Casp-9,and Casp-3,and increased IL-10 levels.Conclusions:Turmeric extract and its compounds have significant hepatoprotective activity and could be further explored for the treatment of liver damage.
基金supported by the Shanghai Rising-Star Program(24QB2702300)Shanghai Municipal Commission of Science and Technology(22N51900100).
文摘Acetaminophen(APAP)used as an antipyretic and analgesic agent can cause acute liver injury(AILI)under overdose.Sanghuangporous vaninii is an edible fungus with abundant metabolites exhibits excellent hepatoprotective activities,but the effect for AILI is not yet fully understood.In this study,the polyphenol rich extract from S.vaninii(PSV)was prepared,with a total phenolic content of 75.72%and 34 compounds.The data of hepatoprotection indicated that PSV obviously alleviated the hepatocellular injury induced by APAP in vivo and in vitro.The protective mechanism of PSV against APAP-induced AILI might be attributed to the activating NRF2/GPX4 pathway.Based on network pharmacology analysis,the active components of PSV such as caffeic acid,osmundacetone and hispolone played a key role in hepatoprotection of PSV.Consequently,this study highlights the protection of PSV on AILI,which provides new insight into bioactivities of S.vaninii.
基金Supported by National Natural Science Foundation of China,No.11772226 and No.81572154.
文摘BACKGROUND In the management of postoperative pain following total joint arthroplasty(TJA),the use of nonsteroidal anti-inflammatory drugs,including acetaminophen,plays a key role in alleviating pain.However,the comparison between intravenous and oral acetaminophen administration in patients undergoing full joint replacement surgery remains controversial.AIM To assess the effectiveness of intravenous and oral acetaminophen in alleviating pain and supporting rehabilitation following TJA.METHODS PubMed,Embase and the Cochrane Library were comprehensively searched to identify cohort studies.The effects of intravenous and oral acetaminophen for managing pain and supporting rehabilitation following TJA were analysed using randomized controlled trials.PRISMA guidelines were followed.The effectiveness of the administration routes was compared based on visual analogue scale(VAS)scores at 24 and 48 h,total morphine usage within 24 h,and total duration of hospital stay.RESULTS The meta-analysis included seven studies comparing intravenous acetaminophen groups and oral acetaminophen groups.The results demonstrated that oral acetaminophen was comparable to intravenous acetaminophen with regard to VAS scores at 24 h and 48 h(P=0.76 and 0.08,respectively).The difference in total morphine use between the two groups was not significant(P=0.22).However,the total hospital stay duration of the intravenous acetaminophen groups was significantly reduced compared to the oral acetaminophen groups(P=0.0005),showing significant advantages in optimizing postoperative recovery and shortening hospitalisation time.CONCLUSION After TJA surgery,intravenous injection of acetaminophen can shorten hospitalisation time and is suitable for rapid analgesia,Oral administration has become the preferred choice for mild cases due to its convenience and economy,providing a basis for clinical drug selection.
基金supported by Xizang Antonomous Region Science and Technology Plan Project(Key Research and Development Program)(No.XZ202201ZY0031G).
文摘Background:Drug-induced liver injury is happening more often,and acetaminophen-induced liver injury is the main cause of drug-induced liver injury.We found that the protective effect of cucurbitacin B(CuB)in acetaminophen-induced liver injury is still unclear.Therefore,we constructed an in vitro model of acute liver injury using BRL-3A cells to explore the possible therapeutic impact and mechanism of CuB.Methods:In this study,cell viability assay,reactive oxygen species assay,immunofluorescence assay,RT-qPCR,and Western blot were used to investigate the therapeutic effect and mechanism of CuB on BRL-3A cells injured by acetaminophen.Results:In the present study,CuB could significantly improve the viability of BRL-3A cells,reduce intracellular lipid reactive oxygen species,aspartate aminotransferase,alanine aminotransferase,and malondialdehyde,and increase the intracellular glutathione and mitochondrial membrane potential.CuB significantly increased the protein levels of intracellular transporters cystine/glutamate transporter Xct(SLC7A11)and glutathione peroxidase 4(GPX4).Further investigation of the mechanism showed that CuB inhibited lipid peroxidation by activating nuclear factor erythroid 2-related factor 2(Nrf2)nuclear translocation and upregulating heme oxygenase 1(HO-1)and NAD(P)H quinone oxidoreductase 1(NQO1).Conclusion:CuB reduces acute liver damage caused by acetaminophen via the Nrf2 pathway.
基金Supported by Guangxi Natural Science Foundation of China,No.2024GXNSFAA010040Special Fund of the Central Government Guiding Local Scientific and Technological Development by Guangxi Science and Technology Department,No.GuikeZY21195024National Natural Science Foundation of China,No.82260499 and No.82460463.
文摘BACKGROUND High levels of acetaminophen(APAP)consumption can result in significant liver toxicity.Mogroside V(MV)is a bioactive,plant-derived triterpenoid known for its various pharmacological activities.However,the impact of MV on acute liver injury(ALI)is unknown.AIM To investigate the hepatoprotective potential of MV against liver damage caused by APAP and to examine the underlying mechanisms.METHODS Mice were divided into three groups:Saline,APAP and APAP+MV.MV(10 mg/kg)was given intraperitoneally one hour before APAP(300 mg/kg)administration.Twenty-four hours after APAP exposure,serum transaminase levels,liver necrotic area,inflammatory responses,nitrotyrosine accumulation,and c-jun-N-terminal kinase(JNK)activation were assessed.Additionally,we analyzed reactive oxygen species(ROS)levels,JNK activation,and cell death in alpha mouse liver 12(AML12)cells.RESULTS MV pre-treatment in vivo led to a reduction in the rise of aspartate transaminase and alanine transaminase levels,mitigated liver damage,decreased nitrotyrosine accumulation,and blocked JNK phosphorylation resulting from APAP exposure,without affecting glutathione production.Similarly,MV diminished the APAP-induced increase in ROS,JNK phosphorylation,and cell death in vitro.CONCLUSION Our study suggests that MV treatment alleviates APAP-induced ALI by reducing ROS and JNK activation.
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.
基金supported by the National Science and Technology Major Project of China(Nos.2018ZX10302206,2017ZX10202203)。
文摘Acetaminophen,also known as N-acetyl-p-aminophenol(APAP),is commonly used as an antipyretic and analgesic agent.APAP overdose can induce hepatic toxicity,known as acetaminophen-induced liver injury(AILI).However,therapeutic doses of APAP can also induce AILI in patients with excessive alcohol intake or who are fasting.Hence,there is a need to understand the potential pathological mechanisms underlying AILI.In this review,we summarize three main mechanisms involved in the pathogenesis of AILI:hepatocyte necrosis,sterile inflammation,and hepatocyte regeneration.The relevant factors are elucidated and discussed.For instance,N-acetyl-p-benzoquinone imine(NAPQI)protein adducts trigger mitochondrial oxidative/nitrosative stress during hepatocyte necrosis,danger-associated molecular patterns(DAMPs)are released to elicit sterile inflammation,and certain growth factors contribute to liver regeneration.Finally,we describe the current potential treatment options for AILI patients and promising novel strategies available to researchers and pharmacists.This review provides a clearer understanding of AILI-related mechanisms to guide drug screening and selection for the clinical treatment of AILI patients in the future.
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.
基金supported by State Project for Essential Drug Research and Development of China(No.20152X09303001)
文摘We investigated the potential hepatoprotective effect of Radix Bupleuri(RB) by inducing acute liver injury(ALI) in an animal model using acetaminophen(APAP) after pretreatment with RB aqueous extract for three consecutive days. Compared to those of the APAP group, the biochemical and histological results of the RB pretreatment group showed lower serum aspartate transaminase(AST) and alanine transaminase(ALT) levels as well as less liver damage. Pharmacokinetic study of the toxicity related marker acetaminophen-cysteine(APC) revealed a lower exposure level in rats, suggesting that RB alleviated APAP-induced liver damage by preventing glutathione(GSH) depletion. The results of cocktail approach showed significant inhibition of CYP2 E1 and CYP3 A activity. Further investigation revealed the increasing of CYP2 E1 and CYP3 A protein was significantly inhibited in pretreatment group,while no obvious effect on gene expression was found. Therefore, this study clearly demonstrates that RB exhibited significant protective action against APAP-induced acute live injury via pretreatment, and which is partly through inhibiting the increase of activity and translation of cytochrome P450 enzymes, rather than gene transcription.
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.
基金supported by the National Natural Sci-ence Foundation of China (No. 21077091,20837002)Qianjiang Talent Project of Zhejiang Province (No.2011R10075)
文摘Commercial available zero valent aluminum under air-equilibrated acidic conditions（ZVAl/H＋/air system） demonstrated an excellent capacity to remove aqueous organic compounds.Acetaminophen（ACTM）,the active ingredient of the over-the-counter drug Tylenol？,is widely present in the aquatic environment and therefore the treatment of ACTM-contaminated water calls for further research.Herein we investigated the oxidative removal of ACTM by ZVAl/H＋/air system and the reaction mechanism.In acidic solutions（pH 3.5）,ZVAl displayed an excellent capacity to remove ACTM.More than 99% of ACTM was eliminated within 16 hr in pH 1.5 reaction solutions initially containing 2.0 g/L aluminum and 2.0 mg/L ACTM at 25 ± 1℃.Higher temperature and lower pH facilitated ACTM removal.The addition of different iron species Fe0,Fe2＋ and Fe3＋ into ZVAl/H＋/air system dramatically accelerated the reaction likely due to the enhancing transformation of H2O2 to HO.via Fenton＇s reaction.Furthermore,the primary intermediate hydroquinone and the anions formate,acetate and nitrate,were identified and a possible reaction scheme was proposed.This work suggested that ZVAl/H＋/air system may be potentially employed to treat ACTM-contaminated water.
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.
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.
基金Project supported by the National Natural Science Foundation of China(No.81322053)the Program for New Century Excellent Talents in University(No.NCET-11-1054)+1 种基金the"Shu Guang"Project of Shanghai Municipal Education Commission and Shanghai Education Development Foundation(No.13SG43)the State Major Science and Technology Special Projects during the 12th Five-Year Plan(No.2012ZX09505001-002),China
文摘Chlorogenic acid（CGA）, a polyphenolic compound, is abundant in fruits, dietary vegetables, and some medicinal herbs. This study investigated the prevention of CGA against acetaminophen（AP）-induced hepatotoxicity and its engaged mechanisms. CGA reversed the decreased cell viability induced by AP in L-02 cells in vitro. In addition, CGA reduced the AP-induced increased serum levels of alanine/aspartate aminotransferase（ALT/AST） in vivo. The effect of CGA on cytochrome P450（CYP） enzymatic（CYP2E1, CYP1A2, and CYP3A4） activities showed that CGA caused very little inhibition on CYP2E1 and CYP1A2 enzymatic activities, but not CYP3A4. The measurement of liver malondialdehyde（MDA）, reactive oxygen species（ROS）, and glutathione（GSH） levels showed that CGA prevented AP-induced liver oxidative stress injury. Further, CGA increased the AP-induced decreased m RNA expression of peroxiredoxin（Prx） 1, 2, 3, 5, 6, epoxide hydrolase（Ephx） 2, and polymerase（RNA） II（DNA directed） polypeptide K（Polr2k）, and nuclear factor erythroid-2-related factor 2（Nrf2）. In summary, CGA ameliorates the AP-induced liver injury probably by slightly inhibiting CYP2E1 and CYP1A2 enzymatic properties. In addition, cellular important antioxidant signals such as Prx1, 2, 3, 5, 6, Ephx2, Polr2 k, and Nrf2 also contributed to the protection of CGA against AP-induced oxidative stress injury.
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 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.
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.
