Reversal Effects of N-Acetyl Cysteine on <i>Moringa oleifera</i>Leaves-Induced Sub-Acute Hepatotoxicity in Wistar Albino Rats

Background: M. oleifera is a highly valued medicinal plant used widely from time immemorial to treat various ailments. However, with continued un-standardized use of the plant leaves, studies have reported organ toxicity to the liver, kidney and the heart. As communities continue to use M. oleifera leaves for its medicinal and nutritional values, there is need to find an antidote for its hepatotoxicity. Aim: The study established the reversal effect of N-Acetyl Cysteine (NAC) on M. oleifera aqueous leaf extract-induced hepatotoxicity in Wistar albino rats. Methods: Twenty-four (24) rats received a toxic dose (8.05 g/kg bwt) of M. oleifera leaf extract for 28 days to cause sub-acute hepatotoxicity. They were divided into 4 groups of 6 rats each. Group I received 1 ml normal (control group), Group II received 1000 ng/kg NAC, Group III received 1200 mg/kg NAC and Group IV received 1500 mg/kg NAC. Another group of 6 rats (Group V) received 0.75 mg/kg Paracetamol to cause hepatotoxicity. Group V (a positive control) received the prescribed clinical dose of 1200 mg/kg NAC which reverses the hepatotoxicity. All the NAC doses were given once a day intragastric for 7 days. On days: 1, 3 and 7 of receiving NAC, liver serum enzymes and bilirubin were measured. On day 7 the animals were sacrificed and liver tissue harvested for histopathology analysis. Results: A dose of 8.05 g/kg of M. oleifera leaf extract and 0.75 mg/kg Paracetamol were able to induce hepatotoxicity in Wister albino rats in 28 days. The M. oleifera extract induced hepatotoxic rats treated with NAC at doses of 1000 mg/kg, 1200 mg/kg and 1500 mg/kg, had a reduction in mean serum liver enzymes, plus reduced mean serum bilirubin levels. The liver histopathological analysis showed reduced inflammation after treatment with NAC for 3 and 7 days in the M. oleifera and paracetamol induced hepatotoxic rats. Conclusion: NAC can reverse M. oleifera leaf aqueous extract-induced sub-acute hepatotoxicity in Wistar Albino rats.

Hepatoprotective effect of Holothuria leucospilota methanolic extract on dimethyl nitrosamine-induced hepatotoxicity in rats

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.

The Protective Effect of Moringa oleifera Leaves Extract on Paracetamol Hepatotoxicity in Male Rats

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. .

Functionalized selenium nanoparticles ameliorated acetaminophen-induced hepatotoxicity through synergistically triggering PKCδ/Nrf2 signaling pathway and inhibiting CYP 2E1

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.

Protective effect of glycyrrhetinic acid against cantharidin-induced hepatotoxicity through reducing oxidative stress in mice

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.

The interaction between polyphyllin I and SQLE protein induces hepatotoxicity through SREBP-2/HMGCR/SQLE/LSS pathway

Polyphyllin I(PPI)and polyphyllin II(PII)are the main active substances in the Paris polyphylla.However,liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechanisms remain to be elucidated.In this work,we found that PPI and PII exposure could induce significant hepatotoxicity in human liver cell line L-02 and zebrafish in a dose-dependent manner.The results of the proteomic analysis in L-02 cells and transcriptome in zebrafish indicated that the hepatotoxicity of PPI and PII was associated with the cholesterol biosynthetic pathway disorders,which were alleviated by the cholesterol biosynthesis inhibitor lovastatin.Additionally,3-hydroxy-3-methy-lglutaryl CoA reductase(HMGCR)and squalene epoxidase(SQLE),the two rate-limiting enzymes in the cholesterol synthesis,selected as the potential targets,were confirmed by the molecular docking,the overexpression,and knockdown of HMGCR or SQLE with siRNA.Finally,the pull-down and surface plasmon resonance technology revealed that PPI could directly bind with SQLE but not with HMGCR.Collectively,these data demonstrated that PPI-induced hepatotoxicity resulted from the direct binding with SQLE protein and impaired the sterol-regulatory element binding protein 2/HMGCR/SQLE/lanosterol synthase pathways,thus disturbing the cholesterol biosynthesis pathway.The findings of this research can contribute to a better understanding of the key role of SQLE as a potential target in drug-induced hepatotoxicity and provide a therapeutic strategy for the prevention of drug toxic effects with similar structures in the future.

Radix Paeoniae Alba attenuates Radix Bupleuri-induced hepatotoxicity by modulating gut microbiota to alleviate the inhibition of saikosaponins on glutathione synthetase

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.

Spatiotemporal pharmacometabolomics based on ambient mass spectrometry imaging to evaluate the metabolism and hepatotoxicity of amiodarone in HepG2 spheroids

Three-dimensional(3D)cell spheroid models combined with mass spectrometry imaging(MSI)enables innovative investigation of in vivo-like biological processes under different physiological and pathological conditions.Herein,airflow-assisted desorption electrospray ionization-MSI(AFADESI-MSI)was coupled with 3D HepG2 spheroids to assess the metabolism and hepatotoxicity of amiodarone(AMI).High-coverage imaging of>1100 endogenous metabolites in hepatocyte spheroids was achieved using AFADESI-MSI.Following AMI treatment at different times,15 metabolites of AMI involved in Ndesethylation,hydroxylation,deiodination,and desaturation metabolic reactions were identified,and according to their spatiotemporal dynamics features,the metabolic pathways of AMI were proposed.Subsequently,the temporal and spatial changes in metabolic disturbance within spheroids caused by drug exposure were obtained via metabolomic analysis.The main dysregulated metabolic pathways included arachidonic acid and glycerophospholipid metabolism,providing considerable evidence for the mechanism of AMI hepatotoxicity.In addition,a biomarker group of eight fatty acids was selected that provided improved indication of cell viability and could characterize the hepatotoxicity of AMI.The combination of AFADESI-MSI and HepG2 spheroids can simultaneously obtain spatiotemporal information for drugs,drug metabolites,and endogenous metabolites after AMI treatment,providing an effective tool for in vitro drug hepatotoxicity evaluation.

Evaluation of Acute and Sub-Acute Oral Toxicities of Momordica foetida Schumach. (Cucurbitaceae) Leaves Methanol Extract in Wistar Rats

Momordica foetida is a plant widely used in tropical Africa to manage gastroenteric diseases. Previous studies demonstrated interesting antibacterial activity against human pathogenic bacteria. However, the security or toxicity of methanol leaf extract has not been determined yet. The aim of this study was to evaluate the acute and sub-acute toxicity of the leaf extract of Momordica foetida. In the acute toxicity study, a single oral dose of 5000 mg/kg body weight was administered to rats which were observed for 14 days in order to identify signs of toxicity or death. In the sub-acute toxicity, the animals were treated with 250, 500 and 1000 mg/kg of the extract for 28 consecutive days. Body weights and behavior were noted throughout the experiment. Upon treatment, blood and urine were collected for hematological and biochemical analysis. Liver, lungs, heart, kidneys, testes and ovaries were analyzed for relative weights and histopathology. The acute toxicity study of M. foetida leaf extract revealed no signs of toxicity related to the treatment, indicating that the median-lethal-dose (LD50) value is greater than 5000 mg/Kg of body weight. In the sub-acute toxicity assay, the extract did not affect the general behavior of animals, meanwhile, it led to a significant increase in the levels of red blood cells, platelets, hemoglobin, granulocytes and Mid-Cells (MIDs). Biochemical parameters showed an increase in total cholesterol, HDL cholesterol, serum urea, serum and urinary glucose and a decrease in urinary proteins, serum creatinine, urinary urea levels, serum activities of AST, ALT and proteins levels, as well as increases in lung, spleen and ovaries relative weight were noticed, all compared to control animals. Histological analysis revealed a normal architecture of kidneys, liver, heart, lung, ovaries and testes. This study provides valuable data on the safety of per os administration of Momordica foetida leaf methanol extract that could be very useful for future assays.

Single-cell RNA sequencing reveals the dynamics of hepatic non-parenchymal cells in autoprotection against acetaminophen-induced hepatotoxicity

Gaining a better understanding of autoprotection against drug-induced liver injury(DILI)may provide new strategies for its prevention and therapy.However,little is known about the underlying mechanisms of this phenomenon.We used single-cell RNA sequencing to characterize the dynamics and functions of hepatic non-parenchymal cells(NPCs)in autoprotection against DILI,using acetaminophen(APAP)as a model drug.Autoprotection was modeled through pretreatment with a mildly hepatotoxic dose of APAP in mice,followed by a higher dose in a secondary challenge.NPC subsets and dynamic changes were identified in the APAP(hepatotoxicity-sensitive)and APAP-resistant(hepatotoxicity-resistant)groups.A chemokine(C-C motif)ligand 2^(+)endothelial cell subset almost disappeared in the APAP-resistant group,and an R-spondin 3^(+)endothelial cell subset promoted hepatocyte proliferation and played an important role in APAP autoprotection.Moreover,the dendritic cell subset DC-3 may protect the liver from APAP hepatotoxicity by inducing low reactivity and suppressing the autoimmune response and occurrence of inflammation.DC-3 cells also promoted angiogenesis through crosstalk with endothelial cells via vascular endothelial growth factor-associated ligand-receptor pairs and facilitated liver tissue repair in the APAP-resistant group.In addition,the natural killer cell subsets NK-3 and NK-4 and the Sca-1^(-)CD62L^(+)natural killer T cell subset may promote autoprotection through interferon-γ-dependent pathways.Furthermore,macrophage and neutrophil subpopulations with anti-inflammatory phenotypes promoted tolerance to APAP hepatotoxicity.Overall,this study reveals the dynamics of NPCs in the resistance to APAP hepatotoxicity and provides novel insights into the mechanism of autoprotection against DILI at a high resolution.

Reflections on the Toxicity and Safety of Traditional Chinese Medicine Combined with the Cases of Nephrotoxicity and Hepatotoxicity

This paper analyzes the relationship between toxicity and safety of traditional Chinese medicine(TCM)based on the cases of current nephrotoxicity and hepatotoxicity,and summarizes the literature on hepatotoxicity and nephrotoxicity.It is found that the main reasons for the toxic reaction of TCM are own factors of drugs,irregular administration of medicine and individual difference.However,as long as the"quality"and"quantity"of TCM are guaranteed,the toxicity of TCM can be controlled within the safety range.

Herbal hepatotoxicity:Challenges and pitfalls of causality assessment methods

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.

Investigation of hepatoprotective activity of Cyathea gigantea(Wall.ex.Hook.)leaves against paracetamol-induced hepatotoxicity in rats

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.

Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests

AIM: To analyze the validity of applied test criteria and causality assessment methods in assumed Herbalife hepatotoxicity with positive reexposure tests. METHODS: We searched the Medline database for suspected cases of Herbalife hepatotoxicity and retrieved 53 cases including eight cases with a positive unintentional reexposure and a high causality level for Herbalife. First, analysis of these eight cases focused on the data quality of the positive reexposure cases, requiring a baseline value of alanine aminotransferase(ALT) < 5 upper limit of normal (N) before reexposure, with Nas the upper limit of normal, and a doubling of the ALT value at reexposure as compared to the ALT value at baseline prior to reexposure. Second, reported methods to assess causality in the eight cases were evaluated, and then the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale validated for hepatotoxicity cases was used for quantitative causality reevaluation. This scale consists of various specific elements with scores provided through the respective case data, and the sum of the scores yields a causality grading for each individual case of initially suspected hepatotoxicity. RESULTS: Details of positive reexposure test conditions and their individual results were scattered in virtually all cases, since reexposures were unintentional and allowed only retrospective rather than prospective assessments. In 1/8 cases, criteria for a positive reexposure were fulfilled, whereas in the remaining cases the reexposure test was classified as negative (n = 1), or the data were considered as uninterpretable due to missing information to comply adequately with the criteria (n = 6). In virtually all assessed cases, liver unspecific causality assessment methods were applied rather than a liver specific method such as the CIOMS scale. Using this scale, causality gradings for Herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n = 3). Confounding variables in- cluded low data quality, alternative diagnoses, poor exclusion of important other causes, and comedication by drugs and herbs in 6/8 cases. More specifically, problems were evident in some cases regarding temporal association, daily doses, exact start and end dates of product use, actual data of laboratory parameters such as ALT, and exact dechallenge characteristics. Short-comings included scattered exclusion of hepatitis A-C, cytomegalovirus and Epstein Barr virus infection with only globally presented or lacking parameters. Hepatitis Evirus infection was considered in one single patient and found positive, infections by herpes simplexvirus and varicella zoster virus were excluded in none. CONCLUSION: Only one case fulfilled positive reexposure test criteria in initially assumed Herbalife hepatotoxicity, with lower CIOMS based causality gradings for the other cases than hitherto proposed.

Hepatoprotective potential of ethanolic extract of Ziziphus oenoplia(L.)Mill roots against antitubercular drugs induced hepatotoxicity in experimental models

Objective:To evaluate the hepatoprotective potential of ethanolic(50%) extract of Ziziphus oenoplia(L.) Mill(Z.oenoplia) root against isoniazid(INH) and rifampicin(RIF) induced liver damage in animal models.Methods:Five groups of six rats each were selected for the study.Ethanolic extract at a dose of 150 and 300 mg/kg as well as silymarin(100 mg/kg) were administered orally once daily for 21 d in INH + RIF treated groups.The serum levels of glutamic oxaloacetic transaminase(SGOT),glutamate pyruvate transaminase(SGPT),alkaline phosphatase (SALP),and bilirubin were estimated along with activities of superoxide dismutase,catalase, glutathione S-transferase,glutathione peroxidase,and hepatic melondialdehyde formation. Histopathological analysis was carried out to assess injury to the liver.Result:The considerably elevated serum enzymatic activities of glutamic oxaloacetic transaminase,glutamate pyruvate transaminase,alkaline phosphatase and bilirubin due to INH + RIF treatment were restored towards norma) in a dose dependent manner after the treatment with ethanolic extract of Z.oenoplia roots.Meanwhile,the decreased activities of superoxide dismutase,catalase, glutathione S-transferase and glutathione peroxidase were also restored towards normal dose dependency.In addition,ethanolic extract also significantly prevented the elevation of hepatic melondialdehyde formation in the liver of INH + RIF intoxicated rats in a dose dependent manner. The biochemical observations were supplemented with histopathological examination of rat liver sections.Conclusions:The results of this study slrongly indicate that ethanolic extract of Z.oenoplia has a potent hepatoprotective action against INH + RIF induced hepatic damage in rats.

Ketoconazole Associated Hepatotoxicity: A Systematic Review and Metaanalysis

Objective To evaluate the incidence of Ketoconazole associated hepatotoxicity and related factors Methods Literature retrieval was conducted by using multi-databases for meta-analysis on Ketoconazole associated hepatotoxicity. The data were collected with a standardized form. Overall estimation of incidence of hepatotoxicity for specific study type was calculated by using a DerSimonian-Laird random-effects model owing to the substantial differences among the studies. Results Totally 204 eligible studies were included in the analysis. The incidence of Ketoconazole associated hepatotoxicity was 3.6%-4.2%. The dosage and duration specific subgroup analyses did not show any significant difference among groups, while the age specific subgroup analysis showed the incidence in children and people aged 〉60 years was 1.4% （95% CI 0.5%-4.2%） and 3.2% （95% Cl： 1.1%-8.7%） respectively. Additionally, the incidence of the hepatotoxicity was higher in people who had oral administration of ketoconazole beyond the provisions of the usage instructions, and the incidence was 5.7% （95% CI： 4.5%-7.2%）. Conclusion Ketoconazole associated hepatotoxicity was common. Off-label use might increase the risk of liver damage. Well-designed large sample studies are needed to identify the risk factors in future.

The protection of Thymus vulgaris leaves alcoholic extract against hepatotoxicity of alcohol in rats

Objective:This study was performed to investigate the protective effect of Thymus vulgaris(T.vulgaris) leaves 70%alcoholic extract against alcohol-mediate hepatotoxicity rats.Methods:The protective effect of extract was investigated at dose of 500 mg/kg/day orally against alcohol-mediate hepatotoxicity using adult male Wister albino rats during 21 days.Protective effect of T.vulgaris extract was evaluated comparing with silymarin standard drug al recommended dose(25 mg/kg/day) orally for 21 days.Results:Alcohol-mediate hepatotoxicity rats(alcohol-control) showed hepatocytes distortion represented as marked increment on liver biomarkers;alkaline phosphatase(ALP),aspartate transaminase(AST) and alanine transaminase(ALT) activities,as well as pronounced reduction on total protein and its fractions albumin and globulin corresponding to normal ranges.Addition to oxidative stress status as depletion on glutathione concentration,catalase(CAT),superoxide dismutase(SOD),glutathione reductase(GR),glutathione-S-transferase(GST) and glutathione peroxidase(GPx)activities,concurrence with augmentation oxidative stress parameters;malondyaldchydc(MDA) and hydrogen peroxide(H_2O_2) concentrations comparing to normal values.Alcohol administration elevated total cholesterol(TC),low density lipoprotein cholesterol(LDL-C) and high density lipoprotein cholesterol(HDL-C) comparing to normal ranges.Co-administration T.vulgaris extract with alcohol showed protective effect on hepatocytes manifested as minimizing on ALP.AST and ALT activities and increment on total protein,albumin and globulin production compared to alcohol-control.Antioxidant enzymes activities;CAT.SOD.GR,GST and GPx were significantly magnified,while MDA and H_2O_2 concentration were lessened corresponding to alcohol-control.Also,lipid profile was markedly improved and risk ratio was lowered compared to alcohol-control.These results were confirmed by normalization of degenerated and fibrotic liver tissue as of alcohol-control.Conclusion:T.vulgaris extract appeared hepatoprotective,hypolipidemic and antioxidant activities on alcohol-mediate hepatotoxicity rats compared to silymarin.

Effect of sub-acute exposure to TiO_2 nanoparticles on oxidative stress and histopathological changes in Juvenile Carp (Cyprinus carpio)

Increasing application of nanotechnology highlights the need to clarify and understand nanotoxicity. Mammalian and in vitro studies have raised concerns about the toxicity of titanium dioxide nanoparticles （TiO2-NPs）, but there are limited data on ecotoxicity to aquatic organisms. In this work, the sub-acute toxicity of TiO2-NPs to carp （Cyprinus carpio） was assessed. Superoxide dismutase （SOD）, catalase （CAT） and peroxidase （POD） activities and lipid peroxidation （LPO） levels in liver, gill and brain tissues of carps varied with concentration of TiO2-NPs suspensions and exposure time （up to 8 d）. As a result, 100 and 200 mg/L TiO2-NPs caused statistically significant decrease in SOD, CAT and POD activities and significant increase in LPO levels in tissues （P 〈 0.05）, suggesting that the fish exposed to these two concentrations of TiO2-NPs suffered from the oxidative stress. The extent of depletion of antioxidant enzymes activities and the elevation of LPO in the liver was the greatest, indicating that the liver might be the most susceptible organ to TiO2-NPs exposure. In addition, carps had gill pathologies including edema and thickening of gill lamellae as well as gill filaments, and liver pathologies including necrotic and apoptosis hepatocytes after exposed to 100 and 200 mg/L TiO2-NPs for 20 d. These results indicated a potential risk from TiO2-NPs released into the aqueous environment.

Protective effects of Balanites aegyptiaca extract, melatonin and ursodeoxycholic acid against hepatotoxicity induced by methotrexate in male rats

Objective: To compare the degree of ameliorative effects of Melatonin(MEL), Ursodeoxycholic acid(UDCA) and Balanites aegyptiaca(BA) against hepatotoxicity induced by MTX for one month. Methods: Eighty adult male rats(Sprague Dawely) weighing(190±10g), were randomly divided into eight equal groups: Control, MTX, MEL, BA, UDCA, MTX+MEL, MTX+BA, MTX+UDCA. Liver function biomarker enzymes, liver tissue oxidative stress parameters, together with total antioxidant capacity and tumor necrosis factor(TNF-α) were determined. Histopathological and immunohistochemistry examinations for TNF-α were also done. Results: MTX showed significant increase in alanine transaminase(ALT), aspartate transaminase(AST), alkaline phosphatase(ALP), gamma glutamyl transferase(GGT), total and direct bilirubin, as well as TNF-α levels, oxidized glutathione(GSSG), malodialdehyde(MDA) and nitric oxide(NO). whereas, total protein, albumin, total antioxidant capacity, reduced glutathione(GSH), glutathione peroxidase(GPx), glutathione reductase(GR), glutathione S-transferase(GST), superoxide dismutase(SOD) and catalase(CAT) levels were significantly decreased in MTX treated group. These alterations were improved by MEL and BA treatment, whereas no improvement was noticed in UDCA treatment. Conclusions: BA may be as promising as MEL in the hepatoprotection against MTX toxicity through their antioxidant and radical scavenging activities. In addition, it is not recommended to co-administer UDCA with MTX as it enhanced inflammation and damage to the liver.

Herbal extracts as hepatoprotectants against acetaminophen hepatotoxicity

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.