Objective:To investigate the protective effects of naringin on doxorubicin(DOX)-induced liver injury.Methods:A total of 50 male rats were allocated into five groups:the control group,the DOX group,the DOX groups treat...Objective:To investigate the protective effects of naringin on doxorubicin(DOX)-induced liver injury.Methods:A total of 50 male rats were allocated into five groups:the control group,the DOX group,the DOX groups treated with 50 mg/kg and 100 mg/kg of naringin by gastric lavage for 10 days,as well as the group treated with 100 mg/kg of naringin alone.Liver and serum samples were collected for biochemical,histopathological,and molecular analyses,including liver enzyme activity,oxidative stress markers,inflammation,apoptosis-related proteins,and DNA damage indicators.Results:Naringin attenuated DOX-induced elevation in liver enzyme activity and inflammation markers while enhancing antioxidant activities.Naringin also activated the Nrf2-HO-1 signaling pathway,with the most pronounced effect in the high-dose naringin group.In addition,naringin modulated apoptotic signaling by downregulating the expression of PI3K-AKT and BAX,and upregulating Bcl-2,as well as reduced the level of 8-OHdG.Histopathological evaluation showed that DOX-induced structural liver alterations,such as cellular degeneration and necrosis,were notably attenuated by naringin treatment.Conclusions:Naringin treatment exerts protective effects against DOX-induced liver injury through its antioxidative,anti-inflammatory,and anti-apoptotic effects.展开更多
[Objectives]To investigate the effects of various extract fractions of Hemsleya sphaerocarpa and their mechanisms of action on hepatotoxicity in normal experimental mice and to provide a scientific foundation for the ...[Objectives]To investigate the effects of various extract fractions of Hemsleya sphaerocarpa and their mechanisms of action on hepatotoxicity in normal experimental mice and to provide a scientific foundation for the clinical application of H.sphaerocarpa.[Methods]The extracts were separated by vacuum rotary evaporation into aqueous,n-butanol,petroleum ether,and ethyl acetate fractions.The resulting extracts from various fractions were subsequently formulated into 10%drug solutions using a normal saline solution.These solutions were administered intragastrically to mice at a dosage of 0.1 mL/10 g once daily.After 14 d of intragastric administration,various indices were assessed,and serum samples were collected from the ocular region of the mice for analysis.[Results]15 g of the aqueous fraction,20 g of the n-butanol fraction,30 g of the petroleum ether fraction,and 20 g of the ethyl acetate fraction were obtained through the vacuum rotary evaporation method.After 14 d of intragastric administration,the serum biochemical indices of the mice were assessed.It was observed that alanine aminotransferase(ALT)levels significantly increased in the mice of experimental group.This finding suggests that the ethyl acetate,petroleum ether,and n-butanol extracts of H.sphaerocarpa may contribute to liver injury in the subjects.After 14 d of drug withdrawal,the ALT level in the ethyl acetate group exhibited a significant decrease,but remained elevated compared to those in the normal saline group.In contrast,the ALT levels in the n-butanol and petroleum ether groups also demonstrated a significant reduction and were marginally lower than those observed in the normal saline group.Furthermore,the body weights of the mice in both the petroleum ether and n-butanol groups did not show any significant changes throughout the duration of drug administration.[Conclusions]The liver injury in mice induced by the ethyl acetate extract of H.sphaerocarpa is characterized as the most severe and challenging to self-heal.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
This study reviews the hepatotoxic chemicals,mechanisms of toxicity,and detoxification methods of Toosendan Fructus(TF).Limonin-type triterpenoids,as primary hepatotoxic components,mediate toxicity though inflammation...This study reviews the hepatotoxic chemicals,mechanisms of toxicity,and detoxification methods of Toosendan Fructus(TF).Limonin-type triterpenoids,as primary hepatotoxic components,mediate toxicity though inflammation,oxidative stress,mitochondrial dysfunction,ferroptosis,and apoptosis.Hepatotoxicity can be mitigated by controlling dosage,using processed forms of the herbs,and through rational herbal compatibility.The review provides insights for enhancing the safety and clinical application of TF.展开更多
Liver disease(LD)is a global health problem caused by multiple factors.At present,there are still obvious problems with limited efficacy and strong side effects of drugs used in the clinical treatment of LD.Therefore,...Liver disease(LD)is a global health problem caused by multiple factors.At present,there are still obvious problems with limited efficacy and strong side effects of drugs used in the clinical treatment of LD.Therefore,it is of great significance to search for effective hepatoprotective drugs from natural products.Geniposide(GS)is a cyclic ether terpenoid compound and a key component in the traditional Chinese medicine Gardenia jasminoides.It has a significant inhibitory effect on LD.However,there is currently no literature systematically analyzing its mechanism of action.To adapt to the environment of new drug research and the need for precision medication,this article summarizes the pathways and possible mechanisms of action discovered by GS in the treatment of LD,based on recent research literature:regulating bile stasis,antioxidant and anti-apoptosis,improving amino acid metabolism,improving energy metabolism,regulating lipid metabolism,anti-inflammatory and analgesic effects,etc.It also summarizes the pharmacokinetics of GS in vivo and discusses the liver toxicity of GS that is positively correlated with dosage.In addition,the existing problems in current research and possible future development directions were also discussed,to lay the foundation for the clinical development of natural product GS.展开更多
Acrylamide is classified as a Class 2A carcinogen and mainly metabolized to produce hepatotoxicity.Phosphatidylcholine is thought to protect the liver from damage,but the protective role of phosphatidylcholine on acry...Acrylamide is classified as a Class 2A carcinogen and mainly metabolized to produce hepatotoxicity.Phosphatidylcholine is thought to protect the liver from damage,but the protective role of phosphatidylcholine on acrylamide-exposed metabolic disorders remains unclear.We investigated protective effect of phosphatidylcholine on the hepatic metabolism in rats exposed to acrylamide using metabolomics and molecular biology approaches.Overall,32 endogenous effect biomarkers and 4 exposure biomarkers were identified as differential signature metabolites responsible for acrylamide exposure and phosphatidylcholine protection.Acrylamide exposure interferes with glutathione metabolism by consuming antioxidant glutathione,cysteine and L-ascorbic acid,and disrupts lipid and carbohydrate metabolism through reducing carnitine content and increasing lipid peroxidation.The phosphatidylcholine treatment reduces the expression of cytochrome P4502E1,alleviates the oxidative stress and inflammation of the liver,and stabilizes the content of glutathione,and thus alleviates the disorder of glutathione.Meanwhile,phosphatidylcholine shifted acrylamide-induced phosphatidylcholine into lysophosphatidylcholine to storage from lysophosphatidylcholine to diacylglycerol,thereby maintaining metabolic homeostasis of glycerophospholipid.The results suggested that phosphatidylcholine supplementation alleviate the disorder of glutathione and lipid metabolism caused by acrylamide exposure,but not significantly change the levels of mercapturic acid adducts of acrylamide,providing the evidence for phosphatidylcholine protection against acrylamide-induced liver injury.展开更多
Background:Sophorae Tonkinensis Radix et Rhizoma(ST,also known as ShanDouGen)pertains to the Sophora genus,which is generally distributed in Southwest China.As a celebrated folk medicine,it has heat-clearing and detox...Background:Sophorae Tonkinensis Radix et Rhizoma(ST,also known as ShanDouGen)pertains to the Sophora genus,which is generally distributed in Southwest China.As a celebrated folk medicine,it has heat-clearing and detoxifying,reducing swelling and soothing pharynx.In recent years,there has been a notable rise in adverse events,including hepatotoxicity,associated with the use of ST,however,the mechanism behind ST-induced hepatotoxicity is unclear.Methods:The effects of ST on liver injury were investigated in vivo.Then,serum and liver samples were then analyzed using high-throughput metabolomics techniques.Furthermore,the application of network pharmacology and multivariate statistical analysis has been instrumental in identifying and predicting biomarkers and targets linked to liver toxicity.Results:In this study,we found that ST extract has a certain degree of damage to the rat liver.Using UPLC-MS/MS techniques,463 compounds were identified from ST,of which 73 compounds were absorbed in the blood of the STH group.Metabolomics results showed that amino acid metabolic biomarkers were associated with liver toxicity induced by ST.Notably,we identified 22 core ingredient as toxic effects Q-markers of ST through correlation analysis between biomarkers and absorbed components.On this basis,it is concluded by network pharmacology that ST may cause liver toxicity through PI3K-Akt signaling pathway,NF-kappa B signaling pathway,MAPK signaling pathway,and other pathways.Conclusion:Our findings also demonstrated that the“chemical composition-blood migration component-liver metabolism”stactics has an enormous potential to discern biomarkers and ingredients,and to elaborate the complexity toxicity mechanism of ST.展开更多
Background:Complementary medicine is an interesting field for extracting bio-active compounds from various plant and animal sources.The hepatoprotective effect of the methanolic extract of a species of sea cucumber ca...Background:Complementary medicine is an interesting field for extracting bio-active compounds from various plant and animal sources.The hepatoprotective effect of the methanolic extract of a species of sea cucumber called Holothuria leu-cospilota in an animal model of liver cancer caused by dimethyl nitrosamine(DMN)was studied.Methods:Wistar female rats were randomly divided into five groups(n=12):control(intact),positive control(received 1%DMN[10 mg/kg/week,intraperitoneally]for 12 weeks),and three treatment groups(received 50,100,and 200 mg/kg/day H.leu-cospilota extract orally for 12 weeks along with intraperitoneal administration of 1%DMN[10 mg/kg/week]).In all groups,ultrasound was performed on the liver every week to check its density.Blood sampling and liver isolation were performed on three occasions,at 4,8,and 12 weeks,to check liver enzymes and the histopathological condition of the liver tissue(every week,four animals from each group were randomly selected).Results:Liver density changes were evident from the eighth week onward in the positive control group.Histopathological results indicated pathologic changes in the positive control group after 4 weeks.The increase in liver enzymes in the posi-tive control group was significantly different from that in the treatment and control groups.Conclusions:We demonstrated the hepatoprotective effect of H.leucospilota on DMN-induced liver damage in rats using biochemical and histological parameters and ultrasonography.More additional research(in silico or in vitro)is needed to find the exact mechanism and the main biological compound in H.leucospilota.展开更多
Selenium nanoparticles(SeNPs)have been demonstrated potential for use in diseases associated with oxidative stress.Functionalized SeNPs with lower toxicity and higher biocompatibility could bring better therapeutic ac...Selenium nanoparticles(SeNPs)have been demonstrated potential for use in diseases associated with oxidative stress.Functionalized SeNPs with lower toxicity and higher biocompatibility could bring better therapeutic activity and clinical application value.Herein,this work was conducted to investigate the protective effect of Pleurotus tuber-regium polysaccharide-protein complex funtionnalized SeNPs(PTR-SeNPs)against acetaminophen(APAP)-induced oxidative injure in HepG2 cells and C57BL/6J mouse liver.Further elucidation of the underlying molecular mechanism,in particular their modulation of Nrf2 signaling pathway was also performed.The results showed that PTR-SeNPs could significantly ameliorate APAP-induced oxidative injury as evidenced by a range of biochemical analysis,histopathological examination and immunoblotting study.PTR-SeNPs could hosphorylate and activate PKCδ,depress Keap1,and increase nuclear accumulation of Nrf2,resulting in upregulation of GCLC,GCLM,HO-1 and NQO-1 expression.Besides,PTR-SeNPs suppressed the biotransformation of APAP to generate intracellular ROS through CYP 2E1 inhibition,restoring the mitochondrial morphology.Furthermore,the protective effect of PTR-SeNPs against APAP induced hepatotoxicity was weakened as Nrf2 was depleted in vivo,indicating the pivotal role of Nrf2 signaling pathway in PTR-SeNPs mediated hepatoprotective efficacy.Being a potential hepatic protectant,PTR-SeNPs could serve as a new source of selenium supplement for health-promoting and biomedical applications.展开更多
In recent years, there has been an increase in concern regarding the effects of paracetamol poisoning on liver tissues, particularly when consumed in large amounts. Some studies have estimated that paracetamol is invo...In recent years, there has been an increase in concern regarding the effects of paracetamol poisoning on liver tissues, particularly when consumed in large amounts. Some studies have estimated that paracetamol is involved in 56% of acute liver diseases, whereas 0.4% of paracetamol overdose cases result in fatal-ity. In this study, the effects of Moringa oleifera on paracetamol toxicity in the liver were explored. It has been demonstrated that Moringa oleifera is highly nu-tritious, contains bioactive molecules, and is therapeutically beneficial. Many studies have shown that Moringa oleifera leaves possess a wide range of biologi-cal properties, including antioxidant, tissue protection, analgesic, antihyperten-sive, and immunomodulatory activities. This study highlights the protective role of Moringa oleifera on handling possible paracetamol hepatotoxicity in male rats. .展开更多
Background:Cantharidin(CTD)is a commonly used natural product with anticancer properties;however,it has significant adverse effects,particularly hepatotoxicity.Glycyrrhetinic acid(GA),the active component of licorice,...Background:Cantharidin(CTD)is a commonly used natural product with anticancer properties;however,it has significant adverse effects,particularly hepatotoxicity.Glycyrrhetinic acid(GA),the active component of licorice,shows potential hepatoprotective effects.The protective effects and mechanism of GA against CTD-induced hepatotoxicity are still unclear.Objective:This study aims to elucidate the effect and mechanism of GA on CTD-induced hepatotoxicity in mice experiments.Methods:Construction of CTD-induced hepatotoxicity models and oral gavage GA intervention for 14 d.The liver index,ALT,AST and LDH levels in the serum of the mice were examined;HE staining was performed to observe pathological changes in the liver.The MDA level and SOD activities in liver tissue were tested.Western blot was conducted to determine Keap1/Nrf2 signaling pathway-related protein expression.Results:The results showed that GA significantly reduced the levels of ALT,AST,and LDH in the serum,which were increased by CTD.Additionally,it also exerted a substantial inhibitory effect on the reduction of SOD activity and the elevation of malondialdehyde content in liver tissue.Notably,the phenomena of nuclear swelling,necrosis,and inflammatory infiltration of liver tissue were significantly attenuated following oral administration of GA in mice.Subsequent research has demonstrated that GA effectively suppressed the CTD-triggered upregulation of Keap1 while increasing the CTD-induced downregulation of Nrf2,HO-1,and NQO1.Conclusion:These findings suggested that GA may protect against CTD-induced hepatotoxicity in mice by exerting antioxidative stress through the Keap1/Nrf2 signaling pathway.展开更多
Nuclear factor erythroid 2-related factor 2 （Nrf2） controls the expression of a wide array of antioxidant response element （ARE）-driven genes, which are involved in stress response and metabolism regulation. The r...Nuclear factor erythroid 2-related factor 2 （Nrf2） controls the expression of a wide array of antioxidant response element （ARE）-driven genes, which are involved in stress response and metabolism regulation. The role of Nrf2/ARE signaling in resistances of cancer cells to radiotherapy and chemotherapy has been widely accepted. However, much less is known about the relevance of Nrf2 to chemotherapy-associated toxicities, such as hepatotoxicity. In the present study, nine chemotherapeutic agents were firstly tested in embryonic fibroblasts （MEFs） and hepatocytes isolated from Nrf2 deficient or wild-type mice. The results indicate that the cytotoxicity of oxaliplatin in hepatocytes was significantly higher than that in MEFs and enhanced by Nrf2 deficiency. Furthermore, oxaliplatin treatment caused more pronounced steatosis and severer liver injury in Nrf2-/- mice compared with wild-type counterparts, as evidenced by dramatically elevated serum transaminase and bilirubin, increased accumulation of fat, inflammatory infiltration and blood congestion. The increased hepatotoxicity in Nrf2 deficient mice was possibly caused by decreased expression of antioxidant genes and glutathione depletion. Our results demonstrated that oxaliplatin-induced hepatotoxicity was significantly impacted by Nrf2 status, therefore Nrf2 could potentially serve as a biomarker to predict or a target to prevent hepatotoxicity of oxaliplatin.展开更多
Objective:To explore the potential mechanism of hepatotoxicity induced by Nux Vomica through network toxicology.Methods:The active components and targets of Nux Vomica were identified and screened by Traditional Chine...Objective:To explore the potential mechanism of hepatotoxicity induced by Nux Vomica through network toxicology.Methods:The active components and targets of Nux Vomica were identified and screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform Database(TCMSP),literature research,PubChem Database,Swiss Target Prediction database,etc.Genecards,pharmGKB and OMIM databases were used to collect hepatotoxicity related targets,then,cross them with active component targets to obtain potential targets of hepatotoxicity caused by Nux Vomica.A"Nux Vomica-Potential active components-Potential targets-Hepatotoxicity"network was constructed with Cytoscape 3.8.0 software.The String 11.0 database was used to construct the protein-protein interaction(PPI)network of the targets and to screen out the core targets.In addition,Gene Ontology(GO)function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were conducted by R software,and then the obtained pathways directly related to hepatotoxicity were integrated.Results:In this study,37 active components were screened via TCMSP and literature research,468 targets for the active components of Nux Vomica were obtained.There were 533 hepatotoxicity-related targets,73 potential targets for hepatotoxicity caused by Nux Vomica,and 26 potential active components,among which Ferulic acid,Novacine,Icajine,Simiarenol were the key active components for hepatotoxicity caused by Nux Vomica,and JUN,RELA,and STAT3 were the core target proteins of hepatotoxicity caused by Nux Vomica.There were 1859 GO entries(P-value<0.05),including 1709 entries of Biological Process(BP),39 entries of Cellular Component(CC),and 111 entries of Molecular Function(MF).KEGG enrichment analysis revealed 145 pathways(value<0.05),of which PI3K/AKT signaling pathway,HIF-1 signaling pathway,EGFR tyrosine kinase inhibitor resistance were strongly correlated with the hepatotoxicity caused by Nux Vomica.Conclusion:Through network toxicology analysis,it was found that lots of potential components in Nux Vomica may be involved in the activation of the excessive inflammatory response,oxidative stress,and the LPS response through multiple targets and multiple pathways,resulting in the generation of hepatotoxicity.展开更多
The present study was designed to evaluate protective activity of an ethanol extract of the stems of Schisandra chinensis(SCE) and explore its possible molecular mechanisms on acetaminophen(APAP) induced hepatotoxicit...The present study was designed to evaluate protective activity of an ethanol extract of the stems of Schisandra chinensis(SCE) and explore its possible molecular mechanisms on acetaminophen(APAP) induced hepatotoxicity in a mouse model. The results of HPLC analysis showed that the main components of SCE included schisandrol A, schisandrol B, deoxyschisandrin, schisan--drin B, and schisandrin C and their contents were 5.83, 7.11, 2.13, 4.86, 0.42 mg·g^(-1), respectively. SCE extract was given for 7 con--secutive days before a single hepatotoxic dose of APAP(250 mg·kg^(-1)) was injected to mice. Our results showed that SCE pretreatment ameliorated liver dysfunction and oxidative stress, which was evidenced by significant decreases in aspartate transaminase(AST), alanine aminotransferase(ALT), malondialdehyde(MDA) contents and elevations in reduced glutathione(GSH) and superoxide dismutase(SOD) levels. These findings were associated with the result that the SCE pretreatment significantly decreased expression levels of 4-hydroxynonenal(4-HNE) and 3-nitrotyrosine(3-NT). SCE also significantly decreased the expression levels of Bax, mitogen-activated protein kinase(MAPK), and cleaved caspase-3 by APAP exposure. Furthermore, supplementation with SCE suppressed the expression levels of inducible nitric oxide synthase(iNOS) and cyclooxygenase-2(COX-2), suggesting alleviation of inflammatory response. In summary, these findings from the present study clearly demonstrated that SCE exerted significant alleviation in APAP-induced oxidative stress, inflammation and apoptosis mainly via regulating MAPK and caspase-3 signaling pathways.展开更多
AIM: To investigate an association between N -acetyltransferase 2 (NAT2 )-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients. METHODS: We studied 100 patients with pulmonary TB treat...AIM: To investigate an association between N -acetyltransferase 2 (NAT2 )-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients. METHODS: We studied 100 patients with pulmonary TB treated with anti-TB drugs including INH. The frequencies and distributions of single nucleotide polymorphisms, haplotypes, and diplotypes of NAT2 were determined by the PCR-restriction fragment length polymorphism method, and the results were compared between TB patients with and without adverse effect, using multivariate logistic regression analysis.RESULTS: Statistical analysis revealed that the frequency of a variant haplotype, NAT2*6A , was signifi cantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity [P = 0.001, odds ratio (OR) = 3.535]. By contrast, the frequency of a wild-type (major) haplotype, "NAT2*4", was signif icantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P < 0.001, OR = 0.265). There was no association between NAT2-haplotypes and skin rash or eosinophilia. CONCLUSION: The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2*4 and NAT2*6A, are useful new biomarkers for predicting anti- TB drug-induced hepatotoxicity.展开更多
The diagnosis of herbal hepatotoxicity or herb induced liver injury(HILI) represents a particular clinical and regulatory challenge with major pitfalls for the causality evaluation.At the day HILI is suspected in a pa...The diagnosis of herbal hepatotoxicity or herb induced liver injury(HILI) represents a particular clinical and regulatory challenge with major pitfalls for the causality evaluation.At the day HILI is suspected in a patient,physicians should start assessing the quality of the used herbal product,optimizing the clinical data for completeness,and applying the Council for International Organizations of Medical Sciences(CIOMS) scale for initial causality assessment.This scale is structured,quantitative,liver specific,and validated for hepatotoxicity cases.Its items provide individual scores,which together yield causality levels of highly probable,probable,possible,unlikely,and excluded.After completion by additional information including raw data,this scale with all items should be reported to regulatory agencies and manufacturers for further evaluation.The CIOMS scale is preferred as tool for assessing causality in hepatotoxicity cases,compared to numerous other causality assessment methods,which are inferior on various grounds.Among these disputed methods are the Maria and Victorino scale,an insufficiently qualified,shortened version of the CIOMS scale,as well as various liver unspecific methods such as thead hoc causality approach,the Naranjo scale,the World Health Organization(WHO) method,and the Karch and Lasagna method.An expert panel is required for the Drug Induced Liver Injury Network method,the WHO method,and other approaches based on expert opinion,which provide retrospective analyses with a long delay and thereby prevent a timely assessment of the illness in question by the physician.In conclusion,HILI causality assessment is challenging and is best achieved by the liver specific CIOMS scale,avoiding pitfalls commonly observed with other approaches.展开更多
Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and post-commercialization regulatory decisions. The diagnosi...Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and post-commercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug’s hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be fine-tuned as further information is collected.展开更多
Fructus Psoraleae,which is commonly consumed for the treatment of osteoporosis,bone fracture,and leucoderma,induces liver injury.This study investigated the pathogenesis of the ethanol extract of Fructus Psoraleae(EEF...Fructus Psoraleae,which is commonly consumed for the treatment of osteoporosis,bone fracture,and leucoderma,induces liver injury.This study investigated the pathogenesis of the ethanol extract of Fructus Psoraleae(EEFP)-induced liver injury in rats.EEFP(1.35,1.80,and 2.25 g·kg^–1)was administrated to Sprague Dawley(SD)rats for 30 d.We measured liver chemistries,histopathology,and quantitative isobaric tags for relative and absolute quantitation(iTRAQ)-based protein profiling.EEFP demonstrated parameters suggestive of liver injury with changes in bile secretion,bile flow rate,and liver histopathology.iTRAQ analysis showed that a total of 4042 proteins were expressed in liver tissues of EEFP-treated and untreated rats.Among these proteins,81 were upregulated and 32 were downregulated in the treatment group.KEGG pathway analysis showed that the drug metabolic pathways of cytochrome P450,glutathione metabolism,glycerolipid metabolism,and bile secretion were enriched with differentially expressed proteins.The expression of key proteins related to the farnesoid X receptor(FXR),i.e.,the peroxisome proliferators-activated receptor alpha(PPAR-α),were downregulated,and multidrug resistance-associated protein 3(MRP3)was upregulated in the EEFP-treated rats.Our results provide evidence that EEFP may induce hepatotoxicity through various pathways.Furthermore,our study demonstrates changes in protein regulation using iTRAQ quantitative proteomics analysis.展开更多
Objective:To investigate the hepatoprotective activity of methanolic leaf extract of Cyathea gigantea(C.gigantea)against paracetamol induced liver damage in rats.Methods:The hepatoprotective activity for plant extract...Objective:To investigate the hepatoprotective activity of methanolic leaf extract of Cyathea gigantea(C.gigantea)against paracetamol induced liver damage in rats.Methods:The hepatoprotective activity for plant extract was investigated for paracetamol induced hepatoxicity in rats.Wislar albino rats of either sex were divided into five groups of 6 animals each and are given orally the following treatment for seven days.The normal control group was given 1%Na.CMC 1mL/kg bw,p.o.Paracetamol at dose of 1g/kg bw,p.o.was given as toxic dose for inducing hepatoloxicity.Silymarin(50mg/kg.p.o.) was given as reference standard.Two doses of C. gigantea extract i.e.,100 mg/kg.p.o.and 200 mg/kg,p.o.were tested for hepatoprotective activity. The treatment was given for seven days and after 24 h of last treatment blood was collected from retro-orbital plexus and analysed for various serum parameters like serum glutamic-oxaloacetic transaminase(SGOT),serum glutamic pyruvic transaminase(SGPT),alkaline phosphatase(ALP),total bilirubin(TB)and total protein(TP)in different groups.Results:The paracetamol intoxication lead to histological and biochemical deteriorations.The treatment with methanolic leaf extract of C.gigantea reduced the elevated levels of SCOT,SGPT,ALP,TB and also reversed the hepatic damage towards normal which further supports the hepatoprotective activity of leaf extract of C.gigantea.Conclusions:The methanolic extract of leaves of C.gigantea at doses of 100 mg/kg bw and 200 mg/kg bw have significant effect on liver of paracetamol induced hepatotoxicity model in rats.展开更多
Radix Bupleuri(RB)is commonly used to treat depression,but it can also lead to hepatotoxicity after longterm use.In many anti-depression prescriptions,RB is often used in combination with Radix Paeoniae Alba(RPA)as an...Radix Bupleuri(RB)is commonly used to treat depression,but it can also lead to hepatotoxicity after longterm use.In many anti-depression prescriptions,RB is often used in combination with Radix Paeoniae Alba(RPA)as an herb pair.However,whether RPA can alleviate RB-induced hepatotoxicity remain unclear.In this work,the results confirmed that RB had a dose-dependent antidepressant effect,but the optimal antidepressant dose caused hepatotoxicity.Notably,RPA effectively reversed RB-induced hepatotoxicity.Afterward,the mechanism of RB-induced hepatotoxicity was confirmed.The results showed that saikosaponin A and saikosaponin D could inhibit GSH synthase(GSS)activity in the liver,and further cause liver injury through oxidative stress and nuclear factor kappa B(NF-kB)/NOD-like receptor thermal protein domain associated protein 3(NLRP3)pathway.Furthermore,the mechanisms by which RPA attenuates RBinduced hepatotoxicity were investigated.The results demonstrated that RPA increased the abundance of intestinal bacteria with glycosidase activity,thereby promoting the conversion of saikosaponins to saikogenins in vivo.Different from saikosaponin A and saikosaponin D,which are directly combined with GSS as an inhibitor,their deglycosylation conversion products saikogenin F and saikogenin G exhibited no GSS binding activity.Based on this,RPA can alleviate the inhibitory effect of saikosaponins on GSS activity to reshape the liver redox balance and further reverse the RB-induced liver inflammatory response by the NFkB/NLRP3 pathway.In conclusion,the present study suggests that promoting the conversion of saikosaponins by modulating gut microbiota to attenuate the inhibition of GSS is the potential mechanism by which RPA prevents RB-induced hepatotoxicity.展开更多
基金supported by the Atatürk University Scientific Research Projects Coordinator(Project No:2020/8737)。
文摘Objective:To investigate the protective effects of naringin on doxorubicin(DOX)-induced liver injury.Methods:A total of 50 male rats were allocated into five groups:the control group,the DOX group,the DOX groups treated with 50 mg/kg and 100 mg/kg of naringin by gastric lavage for 10 days,as well as the group treated with 100 mg/kg of naringin alone.Liver and serum samples were collected for biochemical,histopathological,and molecular analyses,including liver enzyme activity,oxidative stress markers,inflammation,apoptosis-related proteins,and DNA damage indicators.Results:Naringin attenuated DOX-induced elevation in liver enzyme activity and inflammation markers while enhancing antioxidant activities.Naringin also activated the Nrf2-HO-1 signaling pathway,with the most pronounced effect in the high-dose naringin group.In addition,naringin modulated apoptotic signaling by downregulating the expression of PI3K-AKT and BAX,and upregulating Bcl-2,as well as reduced the level of 8-OHdG.Histopathological evaluation showed that DOX-induced structural liver alterations,such as cellular degeneration and necrosis,were notably attenuated by naringin treatment.Conclusions:Naringin treatment exerts protective effects against DOX-induced liver injury through its antioxidative,anti-inflammatory,and anti-apoptotic effects.
基金Supported by Undergraduate Innovation and Entrepreneurship Training Project of Guangxi Zhuang Autonomous Region (S202310599069)Open Fund Project of Key Laboratory of Ethnic Medicine Research in the Youjiang River Basin for Colleges and Universities in Guangxi (yykf2024-02).
文摘[Objectives]To investigate the effects of various extract fractions of Hemsleya sphaerocarpa and their mechanisms of action on hepatotoxicity in normal experimental mice and to provide a scientific foundation for the clinical application of H.sphaerocarpa.[Methods]The extracts were separated by vacuum rotary evaporation into aqueous,n-butanol,petroleum ether,and ethyl acetate fractions.The resulting extracts from various fractions were subsequently formulated into 10%drug solutions using a normal saline solution.These solutions were administered intragastrically to mice at a dosage of 0.1 mL/10 g once daily.After 14 d of intragastric administration,various indices were assessed,and serum samples were collected from the ocular region of the mice for analysis.[Results]15 g of the aqueous fraction,20 g of the n-butanol fraction,30 g of the petroleum ether fraction,and 20 g of the ethyl acetate fraction were obtained through the vacuum rotary evaporation method.After 14 d of intragastric administration,the serum biochemical indices of the mice were assessed.It was observed that alanine aminotransferase(ALT)levels significantly increased in the mice of experimental group.This finding suggests that the ethyl acetate,petroleum ether,and n-butanol extracts of H.sphaerocarpa may contribute to liver injury in the subjects.After 14 d of drug withdrawal,the ALT level in the ethyl acetate group exhibited a significant decrease,but remained elevated compared to those in the normal saline group.In contrast,the ALT levels in the n-butanol and petroleum ether groups also demonstrated a significant reduction and were marginally lower than those observed in the normal saline group.Furthermore,the body weights of the mice in both the petroleum ether and n-butanol groups did not show any significant changes throughout the duration of drug administration.[Conclusions]The liver injury in mice induced by the ethyl acetate extract of H.sphaerocarpa is characterized as the most severe and challenging to self-heal.
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.
文摘This study reviews the hepatotoxic chemicals,mechanisms of toxicity,and detoxification methods of Toosendan Fructus(TF).Limonin-type triterpenoids,as primary hepatotoxic components,mediate toxicity though inflammation,oxidative stress,mitochondrial dysfunction,ferroptosis,and apoptosis.Hepatotoxicity can be mitigated by controlling dosage,using processed forms of the herbs,and through rational herbal compatibility.The review provides insights for enhancing the safety and clinical application of TF.
基金supported by the National Natural Science Foundation of China Key Project(81830110)。
文摘Liver disease(LD)is a global health problem caused by multiple factors.At present,there are still obvious problems with limited efficacy and strong side effects of drugs used in the clinical treatment of LD.Therefore,it is of great significance to search for effective hepatoprotective drugs from natural products.Geniposide(GS)is a cyclic ether terpenoid compound and a key component in the traditional Chinese medicine Gardenia jasminoides.It has a significant inhibitory effect on LD.However,there is currently no literature systematically analyzing its mechanism of action.To adapt to the environment of new drug research and the need for precision medication,this article summarizes the pathways and possible mechanisms of action discovered by GS in the treatment of LD,based on recent research literature:regulating bile stasis,antioxidant and anti-apoptosis,improving amino acid metabolism,improving energy metabolism,regulating lipid metabolism,anti-inflammatory and analgesic effects,etc.It also summarizes the pharmacokinetics of GS in vivo and discusses the liver toxicity of GS that is positively correlated with dosage.In addition,the existing problems in current research and possible future development directions were also discussed,to lay the foundation for the clinical development of natural product GS.
基金supported by the National Natural Science Foundation of China(21976156)。
文摘Acrylamide is classified as a Class 2A carcinogen and mainly metabolized to produce hepatotoxicity.Phosphatidylcholine is thought to protect the liver from damage,but the protective role of phosphatidylcholine on acrylamide-exposed metabolic disorders remains unclear.We investigated protective effect of phosphatidylcholine on the hepatic metabolism in rats exposed to acrylamide using metabolomics and molecular biology approaches.Overall,32 endogenous effect biomarkers and 4 exposure biomarkers were identified as differential signature metabolites responsible for acrylamide exposure and phosphatidylcholine protection.Acrylamide exposure interferes with glutathione metabolism by consuming antioxidant glutathione,cysteine and L-ascorbic acid,and disrupts lipid and carbohydrate metabolism through reducing carnitine content and increasing lipid peroxidation.The phosphatidylcholine treatment reduces the expression of cytochrome P4502E1,alleviates the oxidative stress and inflammation of the liver,and stabilizes the content of glutathione,and thus alleviates the disorder of glutathione.Meanwhile,phosphatidylcholine shifted acrylamide-induced phosphatidylcholine into lysophosphatidylcholine to storage from lysophosphatidylcholine to diacylglycerol,thereby maintaining metabolic homeostasis of glycerophospholipid.The results suggested that phosphatidylcholine supplementation alleviate the disorder of glutathione and lipid metabolism caused by acrylamide exposure,but not significantly change the levels of mercapturic acid adducts of acrylamide,providing the evidence for phosphatidylcholine protection against acrylamide-induced liver injury.
基金supported High-level Innovative Talents of Guizhou Province(QianKeHe platform talents-GCC[2023]047)Guizhou Province"14th Five Year Plan"key discipline of traditional Chinese medicine and ethnic medicine(QZYYZDXK(JS)-2021-03)Guizhou Administration of Traditional Chinese Medicine,Traditional Chinese medicine,ethnic medicine science and technology research project(QZYY-2021-098).
文摘Background:Sophorae Tonkinensis Radix et Rhizoma(ST,also known as ShanDouGen)pertains to the Sophora genus,which is generally distributed in Southwest China.As a celebrated folk medicine,it has heat-clearing and detoxifying,reducing swelling and soothing pharynx.In recent years,there has been a notable rise in adverse events,including hepatotoxicity,associated with the use of ST,however,the mechanism behind ST-induced hepatotoxicity is unclear.Methods:The effects of ST on liver injury were investigated in vivo.Then,serum and liver samples were then analyzed using high-throughput metabolomics techniques.Furthermore,the application of network pharmacology and multivariate statistical analysis has been instrumental in identifying and predicting biomarkers and targets linked to liver toxicity.Results:In this study,we found that ST extract has a certain degree of damage to the rat liver.Using UPLC-MS/MS techniques,463 compounds were identified from ST,of which 73 compounds were absorbed in the blood of the STH group.Metabolomics results showed that amino acid metabolic biomarkers were associated with liver toxicity induced by ST.Notably,we identified 22 core ingredient as toxic effects Q-markers of ST through correlation analysis between biomarkers and absorbed components.On this basis,it is concluded by network pharmacology that ST may cause liver toxicity through PI3K-Akt signaling pathway,NF-kappa B signaling pathway,MAPK signaling pathway,and other pathways.Conclusion:Our findings also demonstrated that the“chemical composition-blood migration component-liver metabolism”stactics has an enormous potential to discern biomarkers and ingredients,and to elaborate the complexity toxicity mechanism of ST.
文摘Background:Complementary medicine is an interesting field for extracting bio-active compounds from various plant and animal sources.The hepatoprotective effect of the methanolic extract of a species of sea cucumber called Holothuria leu-cospilota in an animal model of liver cancer caused by dimethyl nitrosamine(DMN)was studied.Methods:Wistar female rats were randomly divided into five groups(n=12):control(intact),positive control(received 1%DMN[10 mg/kg/week,intraperitoneally]for 12 weeks),and three treatment groups(received 50,100,and 200 mg/kg/day H.leu-cospilota extract orally for 12 weeks along with intraperitoneal administration of 1%DMN[10 mg/kg/week]).In all groups,ultrasound was performed on the liver every week to check its density.Blood sampling and liver isolation were performed on three occasions,at 4,8,and 12 weeks,to check liver enzymes and the histopathological condition of the liver tissue(every week,four animals from each group were randomly selected).Results:Liver density changes were evident from the eighth week onward in the positive control group.Histopathological results indicated pathologic changes in the positive control group after 4 weeks.The increase in liver enzymes in the posi-tive control group was significantly different from that in the treatment and control groups.Conclusions:We demonstrated the hepatoprotective effect of H.leucospilota on DMN-induced liver damage in rats using biochemical and histological parameters and ultrasonography.More additional research(in silico or in vitro)is needed to find the exact mechanism and the main biological compound in H.leucospilota.
基金financially supported by National Natural Science Foundation of China(81700524)Natural Science Foundation of Fujian Province(2022J01866)from Fujian Provincial Department of Science and Technology+1 种基金Key Project of Fujian University of Traditional Chinese Medicine(X2021019)Collaborative Innovation and Platform Establishment Project of Department of Science and Technology of Guangdong Province(2019A050520003)。
文摘Selenium nanoparticles(SeNPs)have been demonstrated potential for use in diseases associated with oxidative stress.Functionalized SeNPs with lower toxicity and higher biocompatibility could bring better therapeutic activity and clinical application value.Herein,this work was conducted to investigate the protective effect of Pleurotus tuber-regium polysaccharide-protein complex funtionnalized SeNPs(PTR-SeNPs)against acetaminophen(APAP)-induced oxidative injure in HepG2 cells and C57BL/6J mouse liver.Further elucidation of the underlying molecular mechanism,in particular their modulation of Nrf2 signaling pathway was also performed.The results showed that PTR-SeNPs could significantly ameliorate APAP-induced oxidative injury as evidenced by a range of biochemical analysis,histopathological examination and immunoblotting study.PTR-SeNPs could hosphorylate and activate PKCδ,depress Keap1,and increase nuclear accumulation of Nrf2,resulting in upregulation of GCLC,GCLM,HO-1 and NQO-1 expression.Besides,PTR-SeNPs suppressed the biotransformation of APAP to generate intracellular ROS through CYP 2E1 inhibition,restoring the mitochondrial morphology.Furthermore,the protective effect of PTR-SeNPs against APAP induced hepatotoxicity was weakened as Nrf2 was depleted in vivo,indicating the pivotal role of Nrf2 signaling pathway in PTR-SeNPs mediated hepatoprotective efficacy.Being a potential hepatic protectant,PTR-SeNPs could serve as a new source of selenium supplement for health-promoting and biomedical applications.
文摘In recent years, there has been an increase in concern regarding the effects of paracetamol poisoning on liver tissues, particularly when consumed in large amounts. Some studies have estimated that paracetamol is involved in 56% of acute liver diseases, whereas 0.4% of paracetamol overdose cases result in fatal-ity. In this study, the effects of Moringa oleifera on paracetamol toxicity in the liver were explored. It has been demonstrated that Moringa oleifera is highly nu-tritious, contains bioactive molecules, and is therapeutically beneficial. Many studies have shown that Moringa oleifera leaves possess a wide range of biologi-cal properties, including antioxidant, tissue protection, analgesic, antihyperten-sive, and immunomodulatory activities. This study highlights the protective role of Moringa oleifera on handling possible paracetamol hepatotoxicity in male rats. .
基金supported by the National Natural Science Foundation of China(Grants no.82060754,81803838)The ability establishment of sustainable use for valuable Chinese medicine resources(2060302)+2 种基金Science and technology project of Guizhou health and Health Committee(gzwkj2021-441)Science and Technology Department of Honghuagang District of Zunyi city of Guizhou province of China([2020]-17)Zunyi Medical University Postgraduate Research Fund(ZYK187).
文摘Background:Cantharidin(CTD)is a commonly used natural product with anticancer properties;however,it has significant adverse effects,particularly hepatotoxicity.Glycyrrhetinic acid(GA),the active component of licorice,shows potential hepatoprotective effects.The protective effects and mechanism of GA against CTD-induced hepatotoxicity are still unclear.Objective:This study aims to elucidate the effect and mechanism of GA on CTD-induced hepatotoxicity in mice experiments.Methods:Construction of CTD-induced hepatotoxicity models and oral gavage GA intervention for 14 d.The liver index,ALT,AST and LDH levels in the serum of the mice were examined;HE staining was performed to observe pathological changes in the liver.The MDA level and SOD activities in liver tissue were tested.Western blot was conducted to determine Keap1/Nrf2 signaling pathway-related protein expression.Results:The results showed that GA significantly reduced the levels of ALT,AST,and LDH in the serum,which were increased by CTD.Additionally,it also exerted a substantial inhibitory effect on the reduction of SOD activity and the elevation of malondialdehyde content in liver tissue.Notably,the phenomena of nuclear swelling,necrosis,and inflammatory infiltration of liver tissue were significantly attenuated following oral administration of GA in mice.Subsequent research has demonstrated that GA effectively suppressed the CTD-triggered upregulation of Keap1 while increasing the CTD-induced downregulation of Nrf2,HO-1,and NQO1.Conclusion:These findings suggested that GA may protect against CTD-induced hepatotoxicity in mice by exerting antioxidative stress through the Keap1/Nrf2 signaling pathway.
基金National Natural Science Foundation of China(Grant No.81272468,81372266,91429305 and 21001011)WU JIEPING Medical Foundation(Grant No.320.6750.12196)
文摘Nuclear factor erythroid 2-related factor 2 （Nrf2） controls the expression of a wide array of antioxidant response element （ARE）-driven genes, which are involved in stress response and metabolism regulation. The role of Nrf2/ARE signaling in resistances of cancer cells to radiotherapy and chemotherapy has been widely accepted. However, much less is known about the relevance of Nrf2 to chemotherapy-associated toxicities, such as hepatotoxicity. In the present study, nine chemotherapeutic agents were firstly tested in embryonic fibroblasts （MEFs） and hepatocytes isolated from Nrf2 deficient or wild-type mice. The results indicate that the cytotoxicity of oxaliplatin in hepatocytes was significantly higher than that in MEFs and enhanced by Nrf2 deficiency. Furthermore, oxaliplatin treatment caused more pronounced steatosis and severer liver injury in Nrf2-/- mice compared with wild-type counterparts, as evidenced by dramatically elevated serum transaminase and bilirubin, increased accumulation of fat, inflammatory infiltration and blood congestion. The increased hepatotoxicity in Nrf2 deficient mice was possibly caused by decreased expression of antioxidant genes and glutathione depletion. Our results demonstrated that oxaliplatin-induced hepatotoxicity was significantly impacted by Nrf2 status, therefore Nrf2 could potentially serve as a biomarker to predict or a target to prevent hepatotoxicity of oxaliplatin.
文摘Objective:To explore the potential mechanism of hepatotoxicity induced by Nux Vomica through network toxicology.Methods:The active components and targets of Nux Vomica were identified and screened by Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform Database(TCMSP),literature research,PubChem Database,Swiss Target Prediction database,etc.Genecards,pharmGKB and OMIM databases were used to collect hepatotoxicity related targets,then,cross them with active component targets to obtain potential targets of hepatotoxicity caused by Nux Vomica.A"Nux Vomica-Potential active components-Potential targets-Hepatotoxicity"network was constructed with Cytoscape 3.8.0 software.The String 11.0 database was used to construct the protein-protein interaction(PPI)network of the targets and to screen out the core targets.In addition,Gene Ontology(GO)function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis were conducted by R software,and then the obtained pathways directly related to hepatotoxicity were integrated.Results:In this study,37 active components were screened via TCMSP and literature research,468 targets for the active components of Nux Vomica were obtained.There were 533 hepatotoxicity-related targets,73 potential targets for hepatotoxicity caused by Nux Vomica,and 26 potential active components,among which Ferulic acid,Novacine,Icajine,Simiarenol were the key active components for hepatotoxicity caused by Nux Vomica,and JUN,RELA,and STAT3 were the core target proteins of hepatotoxicity caused by Nux Vomica.There were 1859 GO entries(P-value<0.05),including 1709 entries of Biological Process(BP),39 entries of Cellular Component(CC),and 111 entries of Molecular Function(MF).KEGG enrichment analysis revealed 145 pathways(value<0.05),of which PI3K/AKT signaling pathway,HIF-1 signaling pathway,EGFR tyrosine kinase inhibitor resistance were strongly correlated with the hepatotoxicity caused by Nux Vomica.Conclusion:Through network toxicology analysis,it was found that lots of potential components in Nux Vomica may be involved in the activation of the excessive inflammatory response,oxidative stress,and the LPS response through multiple targets and multiple pathways,resulting in the generation of hepatotoxicity.
基金supported by the grants of Scientific Research Foundation for the Returned Overseas Chinese Scholars(Jilin Province,2015)Jilin Science&Technology Development Plan(No.20160209008YY)the Program for the Young Top-notch and Innovative Talents of Jilin Agricultural University(2016-2018)
文摘The present study was designed to evaluate protective activity of an ethanol extract of the stems of Schisandra chinensis(SCE) and explore its possible molecular mechanisms on acetaminophen(APAP) induced hepatotoxicity in a mouse model. The results of HPLC analysis showed that the main components of SCE included schisandrol A, schisandrol B, deoxyschisandrin, schisan--drin B, and schisandrin C and their contents were 5.83, 7.11, 2.13, 4.86, 0.42 mg·g^(-1), respectively. SCE extract was given for 7 con--secutive days before a single hepatotoxic dose of APAP(250 mg·kg^(-1)) was injected to mice. Our results showed that SCE pretreatment ameliorated liver dysfunction and oxidative stress, which was evidenced by significant decreases in aspartate transaminase(AST), alanine aminotransferase(ALT), malondialdehyde(MDA) contents and elevations in reduced glutathione(GSH) and superoxide dismutase(SOD) levels. These findings were associated with the result that the SCE pretreatment significantly decreased expression levels of 4-hydroxynonenal(4-HNE) and 3-nitrotyrosine(3-NT). SCE also significantly decreased the expression levels of Bax, mitogen-activated protein kinase(MAPK), and cleaved caspase-3 by APAP exposure. Furthermore, supplementation with SCE suppressed the expression levels of inducible nitric oxide synthase(iNOS) and cyclooxygenase-2(COX-2), suggesting alleviation of inflammatory response. In summary, these findings from the present study clearly demonstrated that SCE exerted significant alleviation in APAP-induced oxidative stress, inflammation and apoptosis mainly via regulating MAPK and caspase-3 signaling pathways.
基金by Grant-in-Aid for Scientif ic Research (Category B, No. 18390168) for K Tsukamoto by the Ministry of Education, Culture, Sports, Science and Technology of Japan
文摘AIM: To investigate an association between N -acetyltransferase 2 (NAT2 )-haplotypes/diplotypes and adverse effects in Japanese pulmonary tuberculosis patients. METHODS: We studied 100 patients with pulmonary TB treated with anti-TB drugs including INH. The frequencies and distributions of single nucleotide polymorphisms, haplotypes, and diplotypes of NAT2 were determined by the PCR-restriction fragment length polymorphism method, and the results were compared between TB patients with and without adverse effect, using multivariate logistic regression analysis.RESULTS: Statistical analysis revealed that the frequency of a variant haplotype, NAT2*6A , was signifi cantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity [P = 0.001, odds ratio (OR) = 3.535]. By contrast, the frequency of a wild-type (major) haplotype, "NAT2*4", was signif icantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P < 0.001, OR = 0.265). There was no association between NAT2-haplotypes and skin rash or eosinophilia. CONCLUSION: The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2*4 and NAT2*6A, are useful new biomarkers for predicting anti- TB drug-induced hepatotoxicity.
文摘The diagnosis of herbal hepatotoxicity or herb induced liver injury(HILI) represents a particular clinical and regulatory challenge with major pitfalls for the causality evaluation.At the day HILI is suspected in a patient,physicians should start assessing the quality of the used herbal product,optimizing the clinical data for completeness,and applying the Council for International Organizations of Medical Sciences(CIOMS) scale for initial causality assessment.This scale is structured,quantitative,liver specific,and validated for hepatotoxicity cases.Its items provide individual scores,which together yield causality levels of highly probable,probable,possible,unlikely,and excluded.After completion by additional information including raw data,this scale with all items should be reported to regulatory agencies and manufacturers for further evaluation.The CIOMS scale is preferred as tool for assessing causality in hepatotoxicity cases,compared to numerous other causality assessment methods,which are inferior on various grounds.Among these disputed methods are the Maria and Victorino scale,an insufficiently qualified,shortened version of the CIOMS scale,as well as various liver unspecific methods such as thead hoc causality approach,the Naranjo scale,the World Health Organization(WHO) method,and the Karch and Lasagna method.An expert panel is required for the Drug Induced Liver Injury Network method,the WHO method,and other approaches based on expert opinion,which provide retrospective analyses with a long delay and thereby prevent a timely assessment of the illness in question by the physician.In conclusion,HILI causality assessment is challenging and is best achieved by the liver specific CIOMS scale,avoiding pitfalls commonly observed with other approaches.
基金Supported partly by research grants from the Agencia Espaoladel Medicamento from the Fondo de Investigación Sanitaria(FIS 04-1688 and FIS 04-1759)
文摘Currently, pharmaceutical preparations are serious contributors to liver disease; hepatotoxicity ranking as the most frequent cause for acute liver failure and post-commercialization regulatory decisions. The diagnosis of hepatotoxicity remains a difficult task because of the lack of reliable markers for use in general clinical practice. To incriminate any given drug in an episode of liver dysfunction is a step-by-step process that requires a high degree of suspicion, compatible chronology, awareness of the drug’s hepatotoxic potential, the exclusion of alternative causes of liver damage and the ability to detect the presence of subtle data that favors a toxic etiology. This process is time-consuming and the final result is frequently inaccurate. Diagnostic algorithms may add consistency to the diagnostic process by translating the suspicion into a quantitative score. Such scales are useful since they provide a framework that emphasizes the features that merit attention in cases of suspected hepatic adverse reaction as well. Current efforts in collecting bona fide cases of drug-induced hepatotoxicity will make refinements of existing scales feasible. It is now relatively easy to accommodate relevant data within the scoring system and to delete low-impact items. Efforts should also be directed toward the development of an abridged instrument for use in evaluating suspected drug-induced hepatotoxicity at the very beginning of the diagnosis and treatment process when clinical decisions need to be made. The instrument chosen would enable a confident diagnosis to be made on admission of the patient and treatment to be fine-tuned as further information is collected.
基金supported by the the National Key Research and Development Program, Specialized Research on Modernization of TCM (Nos. 2018YFC1708006 and 2018YFC1708003)National Major New Drug Creation Special Project “National Drug New Varieties Research and Development and Its Key Innovative Technology Topics” (No. 2017ZX09301060-005)+3 种基金the National Natural Science Foundation of China (No. 81320108029)Tianshan Cedar Plan (No. 2018XS21)National “Major Scientific and Technological Special Project for Significant New Drugs Creation” Project (No. 2015ZX09501004-002-004)Specific Fund for Pub-lic Interest Research of Traditional Chinese Medicine, Ministry of Finance of China (No. 201507004-002)。
文摘Fructus Psoraleae,which is commonly consumed for the treatment of osteoporosis,bone fracture,and leucoderma,induces liver injury.This study investigated the pathogenesis of the ethanol extract of Fructus Psoraleae(EEFP)-induced liver injury in rats.EEFP(1.35,1.80,and 2.25 g·kg^–1)was administrated to Sprague Dawley(SD)rats for 30 d.We measured liver chemistries,histopathology,and quantitative isobaric tags for relative and absolute quantitation(iTRAQ)-based protein profiling.EEFP demonstrated parameters suggestive of liver injury with changes in bile secretion,bile flow rate,and liver histopathology.iTRAQ analysis showed that a total of 4042 proteins were expressed in liver tissues of EEFP-treated and untreated rats.Among these proteins,81 were upregulated and 32 were downregulated in the treatment group.KEGG pathway analysis showed that the drug metabolic pathways of cytochrome P450,glutathione metabolism,glycerolipid metabolism,and bile secretion were enriched with differentially expressed proteins.The expression of key proteins related to the farnesoid X receptor(FXR),i.e.,the peroxisome proliferators-activated receptor alpha(PPAR-α),were downregulated,and multidrug resistance-associated protein 3(MRP3)was upregulated in the EEFP-treated rats.Our results provide evidence that EEFP may induce hepatotoxicity through various pathways.Furthermore,our study demonstrates changes in protein regulation using iTRAQ quantitative proteomics analysis.
基金Supported by University Grants Commission.(No.Fdb/Pharmacy/C6102/2008-2010/5162)
文摘Objective:To investigate the hepatoprotective activity of methanolic leaf extract of Cyathea gigantea(C.gigantea)against paracetamol induced liver damage in rats.Methods:The hepatoprotective activity for plant extract was investigated for paracetamol induced hepatoxicity in rats.Wislar albino rats of either sex were divided into five groups of 6 animals each and are given orally the following treatment for seven days.The normal control group was given 1%Na.CMC 1mL/kg bw,p.o.Paracetamol at dose of 1g/kg bw,p.o.was given as toxic dose for inducing hepatoloxicity.Silymarin(50mg/kg.p.o.) was given as reference standard.Two doses of C. gigantea extract i.e.,100 mg/kg.p.o.and 200 mg/kg,p.o.were tested for hepatoprotective activity. The treatment was given for seven days and after 24 h of last treatment blood was collected from retro-orbital plexus and analysed for various serum parameters like serum glutamic-oxaloacetic transaminase(SGOT),serum glutamic pyruvic transaminase(SGPT),alkaline phosphatase(ALP),total bilirubin(TB)and total protein(TP)in different groups.Results:The paracetamol intoxication lead to histological and biochemical deteriorations.The treatment with methanolic leaf extract of C.gigantea reduced the elevated levels of SCOT,SGPT,ALP,TB and also reversed the hepatic damage towards normal which further supports the hepatoprotective activity of leaf extract of C.gigantea.Conclusions:The methanolic extract of leaves of C.gigantea at doses of 100 mg/kg bw and 200 mg/kg bw have significant effect on liver of paracetamol induced hepatotoxicity model in rats.
基金This study is funded by the National Nature Science Foundation of China(Grant Nos.:82074323,and 81673572)Key Research and Development Program of Shanxi Province(Program No.:202102130501010)+2 种基金The major science and technology project for“Significant New Drugs Creation”(Project No.:2017ZX09301047)Research Project Supported by Shanxi Scholarship Council of China(Project No.:2020019)The special fund for Science and Technology Innovation Teams of Shanxi Province(Grant No.:202204051002011).
文摘Radix Bupleuri(RB)is commonly used to treat depression,but it can also lead to hepatotoxicity after longterm use.In many anti-depression prescriptions,RB is often used in combination with Radix Paeoniae Alba(RPA)as an herb pair.However,whether RPA can alleviate RB-induced hepatotoxicity remain unclear.In this work,the results confirmed that RB had a dose-dependent antidepressant effect,but the optimal antidepressant dose caused hepatotoxicity.Notably,RPA effectively reversed RB-induced hepatotoxicity.Afterward,the mechanism of RB-induced hepatotoxicity was confirmed.The results showed that saikosaponin A and saikosaponin D could inhibit GSH synthase(GSS)activity in the liver,and further cause liver injury through oxidative stress and nuclear factor kappa B(NF-kB)/NOD-like receptor thermal protein domain associated protein 3(NLRP3)pathway.Furthermore,the mechanisms by which RPA attenuates RBinduced hepatotoxicity were investigated.The results demonstrated that RPA increased the abundance of intestinal bacteria with glycosidase activity,thereby promoting the conversion of saikosaponins to saikogenins in vivo.Different from saikosaponin A and saikosaponin D,which are directly combined with GSS as an inhibitor,their deglycosylation conversion products saikogenin F and saikogenin G exhibited no GSS binding activity.Based on this,RPA can alleviate the inhibitory effect of saikosaponins on GSS activity to reshape the liver redox balance and further reverse the RB-induced liver inflammatory response by the NFkB/NLRP3 pathway.In conclusion,the present study suggests that promoting the conversion of saikosaponins by modulating gut microbiota to attenuate the inhibition of GSS is the potential mechanism by which RPA prevents RB-induced hepatotoxicity.
