The potential effect of berberine in mercury-induced hepatorenal toxicity in albino rats

Mercury (Hg) is the third most dangerous heavy metal after arsenic and lead. Mercury’s toxicity brings serious risks to health through negative pathological and biochemical effects. The study was designed to investigate the possible protective role of berberine (BN) in mercuric chloride (HgCl₂) induced oxidative stress in hepatic and renal tissues. Adult male albino Wistar rats were exposed to mercuric chloride (HgCl₂; 0.4 mg/kg bwt) for 7 days. Treatment with HgCl₂ induced oxidative stress by increasing lipid peroxidation and nitric oxide production along with a concomitant decrease in glutathione and various antioxidant enzymes, namely superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. HgCl₂ intoxication increased the activities of liver enzymes and the bilirubin level, in addition to the levels of urea and creatinine in serum. BN (100 mg/kg bwt) treatment inhibited lipid peroxidation and nitric oxide production, whereas it increased glutathione content. Activities of antioxidants enzymes, superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, were also restored concomitantly when compared to control after BN administration. BN also inhibited the apoptotic effect of HgCl₂ by increasing the expression of Bcl-2 protein in liver and kidney. Histopathological examination of the liver and kidney tissues proved the protective effect of BN against HgCl₂ toxicity. These results demonstrated that BN augments antioxidant defense against HgCl₂-induced toxicity and provides evidence that it has therapeutic potential as hepato- and reno-protective agent.     

Cytoprotective effects of DL-alpha-lipoic acid or squalene on cyclophosphamide-induced oxidative injury: An experimental study on rat myocardium,testicles and urinary bladder

The present study aimed to evaluate the role of DL-alpha-lipoic acid (LA) and squalene (SQ) on oxidative cardiac, testicular and urotoxic damage induced by cyclophosphamide (CP). Male Wistar rats were divided into four groups; three groups received a single intraperitoneal injection of CP (200 mg/kg BW) to induce toxicity, and two of these groups received either LA (35 mg/kg BW) or SQ (0.4 ml/rat) orally 7 days before and 7 days after CP injection. A vehicle-treated control group was also included. Oxidative damage was observed by decreased serum total antioxidant capacity (TAC) level and abnormal alterations in glutathione peroxidase (GPx) and glutathione reductase (GR) activities, levels of glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO) and calcium (Ca⁺²) in the heart, testes and urinary bladder of CP-administered rats. Cardiac marker enzyme activities; creatine phosphokinase (CPK), lactate dehydrogenase (LDH), and aspartate transaminase (AST) showed severe declines whereas testicular markers; sorbitol dehydrogenase (SDH), γ-glutamyl transferase (γ-GT), acid and alkaline phosphatases (ACP and ALP), serum testosterone (T) level and haemoglobin (Hb) absorbance were abnormal. Histopathological observations were also altered. These CP-induced pathological alterations were attenuated by treatment with LA or SQ. These findings highlight the efficacy of LA and SQ as cytoprotectants in CP-induced toxicity.     

Fisetin,a tetra hydroxy flavone recuperates antioxidant status and protects hepatocellular ultrastructure from hyperglycemia mediated oxidative stress in streptozotocin induced experimental diabetes in rats

Oxidative stress is a biological entity quoted as accountable for several pathological conditions including diabetes mellitus. Chronic hyperglycemia in diabetes is associated with oxidative stress mediated tissue damage. The present study is aimed to explore the role of fisetin, in ameliorating hyperglycemia-mediated oxidative damage to liver in streptozotocin induced diabetic rats. In addition to the levels of blood glucose, plasma insulin, glycosylated hemoglobin, the extent of oxidative stress was assessed by hepatic lipid peroxides and hydroperoxides. The levels of reduced glutathione and the activities of enzymatic antioxidants were determined in the liver tissues. The activities of serum aminotransferases and alkaline phosphatase were assayed. A portion of liver was processed for histological and ultrastructural studies. Oral administration of fisetin (10 mg/kg b.w.) to diabetic rats decreased the levels of blood glucose and glycosylated hemoglobin and increased the plasma insulin level. A reduction in lipid peroxides and hydroperoxides were observed. The diminished activities of antioxidant enzymes and reduced glutathione in diabetic rats were improved upon fisetin administration. Thus, the results of the present study indicate that fisetin treatment protects the hepatocytes by improving the antioxidant competence in hepatic tissues of diabetic rats which is further evidenced from histological and ultra structural observations.     

Antioxidant biomarker survey ensuing long-term selenium withdrawal in Acipenser baeri fed Se-cysteine diets

Two selenium withdrawal periods, 30 and 90 days, were considered for sturgeon fed 90 days three Se-cysteine diets (1.25, 5, 20 mg kg⁻¹). Subsequently Acipenser baeri was fed the previous control diet (0.32 mg Se kg⁻¹) for 90 days. Levels of superoxide dismutase, catalase, glutathione peroxidases, glutathione reductase, glyoxalase-II and malondialdehyde were determined in liver and kidney. Chemical analyses were carried out for the same tissues and for muscle. A reduction of Se levels in all tissues was recorded and the metalloid concentration decreased more quickly in liver than in kidney and muscle. At the end of the withdrawal Se concentration in muscle remained high in specimens previously fed 20 mg Se kg⁻¹ diet, and disturbance of key antioxidant enzymes was recorded in liver and kidney. Moreover, alterations in glutathione peroxidases, and glyoxalase-II activities persisted even after 90 withdrawal days and were indicative of oxidative stress induced by Se-cysteine concentrations.     

The ameliorating effects of selenium and vitamin C against fenitrothion-induced blood toxicity in Wistar rats

Fenitrothion is widely used organophosphate pesticide in agriculture and health programs, but besides, it causes several toxic effects. The present study was designed to evaluate the possible protective effects of selenium (0.5 mg/kg b.w.) and vitamin C (100 mg/kg b.w) on altered haematological, biochemical and oxidative stress parameters in the blood of rats orally treated with fenitrothion (20 mg/kg b.w) for 30 days. Fenitrothion caused changes in body weight, food and water intake, and some haematological and biochemical parameters. Fenitrothion altered the glutathione redox status (GSH and GSSG) and decreased activity of antioxidant enzymes (GSH-Px, GST, SOD and CAT), leading to a lipid peroxidation. Selenium and vitamin C, by improving the activity of antioxidants, reduced oxidative stress and a lipid peroxidation, maintaining the values of examined parameters to optimal levels. Therefore, selenium and vitamin C could be useful in providing protection of exposed non-target organisms including people from fenitrothion.     

Failure of recovery from lead induced hepatoxicity and disruption of erythrocyte antioxidant defence system in Wistar rats

Lead acetate (PbA) is one of the major environmental contaminants with grave toxicological consequences both in the developing and developed countries. The liver and erythrocyte antioxidant status and markers of oxidative were assessed. Exposure of rats to PbA led to significant decline (p < 0.05) in hepatic and erythrocyte glutathione peroxidase (GPx), glutathione S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH) content. Similarly, malondialdehyde (MDA) and H₂O₂ concentrations were significantly (p < 0.05) elevated. Histopathology and immunohistology of liver of rats exposed to PbA showed focal areas of necrosis and COX-2 expression after 6 weeks of PbA withdrawal. Taken together, hepatic and erythrocytes antioxidant defence system failed to recover after withdrawal of the exposed PbA for the period of the study. In conclusion, experimental animals exposed to PbA did not recover from hepatotoxicity and disruption of erythrocyte antioxidant defence system via free radical generation and oxidative stress.     

Studies on comparative efficacy of α-linolenic acid and α-eleostearic acid on prevention of organic mercury-induced oxidative stress in kidney and liver of rat

The present study was undertaken to evaluate the effect of α-linolenic acid and α-eleostearic acid, two isomers of linolenic acid, against oxidative stress induced by organic mercury in kidney and liver cells of rat. Male albino rats were divided into six groups. Groups 1, 2 were normal control and methyl mercury chloride (MeHgCl) treated (5 mg/kg BW/day) control, respectively. Groups 3, 4, 5 and 6 were orally treated with different doses of two fatty acids (0.5% and 1.0% of total lipid given for each isomer) along with MeHgCl (5 mg/kg BW). Results showed that activity of antioxidant enzymes viz. catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), reduced glutathione (GSH) in liver and kidney decreased significantly due to oxidative stress generated by MeHg. Administration of the linolenic acid isomers almost restored all the altered parameters and also reduced lipid peroxidation and leakage of trans-aminase enzymes from liver to blood due to liver injury when administrated in higher doses. Histopathology of liver and kidney cells showed that administration of α-linolenic acid significantly reduced the damage generated by MeHg. Thus, α-linolenic acid and α-eleostearic acid could serve as cost-effective and natural phytochemical preparation to protect against the adverse effects caused by organic mercury in human.     

Acute effects of diesel exhaust particles and cisplatin on oxidative stress in cultured human kidney (HEK 293) cells,and the influence of curcumin thereon

Particulate air pollution with particle diameters less than 2.5 μm contribute to respiratory and extra-respiratory morbidity and mortality. We have recently reported the first in vivo experimental evidence that Diesel exhaust particles (DEP) in the lung aggravated the renal, pulmonary, and systemic effects of cisplatin (CP)-induced acute renal failure in rats. This in vitro study sought to determine whether and to what extent does DEP exposure exacerbate the effects of CP-induced oxidative stress in human embryonic kidney (HEK-293) cells, and to examine if these effects could be mitigated/prevented with curcumin (the yellow pigment isolated from turmeric). Cells viability, cysteine uptake and oxidative stress indices [glutathione (GSH), total antioxidant capacity (TAC), and the activities of antioxidant enzymes (catalase; glutathione peroxidase; superoxide dismutase)] were evaluated in all study groups. DEP aggravated the CP- induced HEK-293 cells toxicity, as evidenced by decreasing cell viability and by inducing oxidative stress (GSH depletion, TAC impairment, and antioxidant enzymes inhibition). DEP, but not CP, significantly reduced cysteine uptake. Curcumin prevented the observed DEP and CP-induced cellular insults. These findings suggest that DEP augmented the CP-induced toxicity in HEK-293 cells. Curcumin exhibited a strong potential for protection against DEP and CP-induced cytotoxicity.     

Zidovudine and isoniazid induced liver toxicity and oxidative stress: Evaluation of mitigating properties of silibinin

HIV/AIDS patients are more prone for opportunistic TB infections and they are administered the combined regimen of anti-retroviral drug zidovudine (AZT) and isoniazid (INH) for therapy. However, AZT + INH treatment has been documented to induce injury and remedial measures to prevent this adversity are not clearly defined. Silibinin (SBN) is a natural hepatoprotective principle isolated from medicinal plant Silybum marianum and is currently used for therapy of various liver diseases. This study investigate the hepatotoxic potentials of AZT alone, INH alone and AZT + INH treatments and the mitigating potentials of SBN against these drugs induced toxic insults of liver in rats. Separate groups of rats (n = 6 in each group) were administered AZT alone (50 mg/kg b.w.), INH alone (25 mg/kg, b.w.), AZT + INH (50 mg/kg, b.w. and 25 mg/kg, b.w.), SBN alone (100 mg/kg, b.w.) and SBN + AZT + INH daily for sub-chronic period of 45 days orally. The control rats received saline/propylene glycol. INH alone and AZT + INH-induced parenchymal cell injury and cholestasis of liver was evidenced by highly significant increase in the activities of marker enzymes (aspartate and alanine transaminase, alkaline phosphatase, argino succinic acid lyase), bilirubin, protein, oxidative stress parameters (lipid peroxidation, superoxide dismutase, catalase, reduced glutathione, vitamins C and E) and membrane bound ATPases were evaluated in serum/liver tissue homogenates. Histopathological studies show ballooning degradation, inflammatory lesions, lipid deposition and hydropic changes in the liver tissue. All the above biochemical and pathological changes induced by AZT + INH treatments were mitigated in rats receiving SBN simultaneously with these hepatotoxins, indicating its hepatoprotective and antioxidant potentials against AZT + INH-induced hepatotoxicity. The moderate hepatoprotective and oxidant potentials of SBN could be due to its low bioavailability and this deficiency could be prevented by supplementation of phosphatidylcholines and studies are warranted on these lines to improve the therapeutic efficiency of SBN.     

Effect of 4-methylpyrazole on antioxidant enzyme status and lipid peroxidation in the liver of rats after exposure to ethylene glycol and ethyl alcohol

BackgroundThe aim of the conducted studies was to evaluate the effect of 4-methylpyrazole, increasingly used in detoxifying treatments after ethylene glycol poisoning, on the activity of some antioxidant enzymes and lipid peroxidation formation in the liver of rats after experimental co-exposure to ethylene glycol and ethyl alcohol.MethodsThe trials were conducted on adult male Wistar rats. Ethylene glycol (EG) at the dose of 3.83 g/kg bw and ethyl alcohol (EA) at the dose of 1 g/kg bw were administered po, and 4-methylpyrazole (4-MP) at the dose of 0.01 g/kg bw was administered ip. Parameters of antioxidant balance were evaluated in hepatic cytosol, including the activity of the following enzymes: glutathione S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx) and lipid peroxidation level (TBARS).ResultsThe results suggest that evaluation of the effects of administrated 4-MP after co-exposure to EG and EA in the liver revealed statistically significant changes on antioxidant enzyme system and malondialdehyde formation.ConclusionThe changes in biomarkers activity indicate a greater production of free radicals which exceeds the capability of antioxidant system, appearing with oxidative stress in the group of animals treated by 4-MP combined with EG and EA.     

Protective effects of selenium on oxidative damage and oxidative stress related gene expression in rat liver under chronic poisoning of arsenic

Arsenic (As) is a toxic metalloid existing widely in the environment, and chronic exposure to it through contaminated drinking water has become a global problem of public health. The present study focused on the protective effects of selenium on oxidative damage of chronic arsenic poisoning in rat liver. Rats were divided into four groups at random and given designed treatments for 20 weeks. The oxidative damage of liver tissue was evaluated by lipid peroxidation and antioxidant enzymes. Oxidative stress related genes were detected to reflect the liver stress state at the molecular level. Compared to the control and Na₂SeO₃ groups, the MDA content in liver tissue was decreased and the activities of antioxidant enzymes were increased in the Na₂SeO₃ intervention group. The mRNA levels of SOD1, CAT, GPx and Txnrd1 were increased significantly (P < 0.05) in the combined Na₂SeO₃ + NaAsO₂ treatment group. The expressions of HSP70 and HO-1 were significantly (P < 0.05) increased in the NaAsO₂ group and reduced in the combined treatment group. The results indicate that long-term intake of NaAsO₂ causes oxidative damage in the rat liver, and Na₂SeO₃ protects liver cells by adjusting the expression of oxidative stress related genes to improve the activities of antioxidant enzymes.     

N-acetylcysteine protects against fluoride-induced oxidative damage in primary rat hepatocytes

Fluoride induces the overproduction of free radicals, which might in turn affect various biochemical parameters. Therefore, the aim of this study was to elucidate the role of N-acetylcysteine (NAC) in decreasing fluoride-induced oxidative stress. The fluoride intoxicated (0.002; 0.082; 0.164 mmol/l) rat hepatocytes was pre-treated (60 min) and simultaneously treated with NAC (1 mmol/l). The resulting levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and intracellular reduced glutathione (GSH) were measured along with the total antioxidant status (TAS) to determine whether NAC treatment reduced cell damage and/or the antioxidant state. These results suggest that NAC pre-treatment provides protection against fluoride-induced oxidative stress in hepatocytes.     

Brain and lungs of rats are differently affected by cigarette smoke exposure: Antioxidant effect of an organoselenium compound

Cigarette smoke exposure has been associated with oxidative stress in several organs. Antioxidant effect of diphenyl diselenide (PhSe)₂, an organoselenium compound, on oxidative damage induced by sub-chronic cigarette smoke exposure in brain and lungs of rats was investigated. Animals were exposed 5 times/week to one, two, three and four cigarettes for exposure periods of 15 min during the first, second, third and fourth weeks. Reactive species (RS) levels, enzymatic antioxidant defenses (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST) activities) and non-enzymatic antioxidant defenses (ascorbic acid and non-protein thiol (NPSH) levels) were examined in brain and lungs of rats. An increase in RS levels induced by cigarette smoke in both tissues of rats was demonstrated. Cigarette smoke altered enzymatic antioxidant defenses (GST, CAT and SOD activities) in both tissues, and reduced the non-enzymatic antioxidant defenses in lungs. (PhSe)₂ (0.5 mg/kg/day, 5 times/week) restored RS levels and antioxidant defenses in brain of rats exposed to cigarette smoke. (PhSe)₂ treatment increased NPSH levels, GST and GR activities per se in lungs of rats. In conclusion, sub-chronic exposure to cigarette smoke caused alterations in antioxidant defense system and a tissue-specific oxidative stress in brain and lungs of rats. (PhSe)₂ restored antioxidant defenses in lungs and brain of rats.     

Protective effects of curcumin against oxidative stress parameters and DNA damage in the livers and kidneys of rats with biliary obstruction

Curcumin, a most active antioxidant compound, has been suggested to have potential beneficial effects against most metabolic and psychological disorders, including cholestasis. In the present study, the effects of curcumin against oxidative stress and DNA damage induced by bile duct ligation (BDL) in Wistar albino rats for 14 days were investigated. The rats were divided into three following groups: Sham group, the BDL group and the BDL + curcumin group. A daily dose of 50 mg/kg curcumin was given to the BDL + curcumin group intragastrically for 14 days. The biomarkers of hepatocellular damage were decreased in the BDL + curcumin group compared to the BDL group, indicating that curcumin recovered the liver functions. DNA damage as assessed by the alkaline comet assay was also found to be low in the BDL + curcumin group. Curcumin significantly reduced malondialdehyde and nitric oxide levels, and enchanced reduced glutathione levels and catalase, superoxide dismutase, and glutathione S-transferase enzymes activities in the livers and kidneys of BDL group. Curcumin treatment in BDL group was found to decrease tumor necrosis factor-alpha levels in the livers of rats. These results suggest that curcumin might have protective effects on the cholestasis-induced injuries in the liver and kidney tissues of rats.     

Quercetin protects against ethanol-induced oxidative damage in rat primary hepatocytes

The pathogenesis and progression of alcoholic liver disease (ALD) are associated with free radical injury and oxidative stress, which could be partially attenuated by antioxidants and free radical scavengers. Quercetin, one of the most widely distributed flavonoids in plants, is a natural antioxidant. The hypothesis that quercetin could prevent the ethanol-induced oxidative damage in hepatocytes was investigated. The ethanol-intoxicated (100 mM for 8 h) rat primary hepatocytes were post-treated (2 h), simultaneously treated or pre-treated (2 h) with quercetin respectively, while the time-dependent (0.5–8 h) and dose-dependent (25–200 μM) quercetin pre-treatment were used in the present study. The parameters of lactate dehydrogenase (LDH), aspartate transaminase (AST), malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were determined to address the alterations of cell damage and antioxidant state after quercetin intervention. The toxic insult of ethanol to hepatocytes was challenged by quercetin and these parameters almost returned to the level of control group when hepatocytes were pre-treated with quercetin at the dose of 50 μM for 2–4 h before ethanol exposure. In conclusion, quercetin pre-treatment provided protection against ethanol-induced oxidative stress in hepatocytes and may be used as a new natural drug for the prevention and/or treatment of ALD.     

Royal jelly attenuates azathioprine induced toxicity in rats

In the present study, we investigated the potential protective effects of royal jelly against azathioprine-induced toxicity in rat. Intraperitoneal administration of azathioprine (50 mg/kg B.W.) induced a significant decrease in RBCs count, Hb concentration, PCV%, WBCs count, differential count and platelet count, hepatic antioxidant enzymes (reduced glutathione and glutathione s-transferase) and increase of serum transaminases (alanine aminotransferase and aspartate aminotransferase enzymes) activities, alkaline phosphatase and malondialdehyde formation. Azathioprine induced hepatotoxicity was reflected by marked pathological changes in the liver. Oral administration of royal jelly (200 mg/kg B.W.) was efficient in counteracting azathioprine toxicity whereas it altered the anemic condition, leucopenia and thrombocytopenia induced by azathioprine. Furthermore, royal jelly exerted significant protection against liver damage induced by azathioprine through reduction of the elevated activities of serum hepatic enzymes. Moreover, royal jelly blocked azathioprine-induced lipid peroxidation through decreasing the malondialdehyde formation. In conclusion, royal jelly possesses a capability to attenuate azathioprine-induced toxicity.     

Effect of exposure to fluoride and acetaminophen on oxidative/nitrosative status of liver and kidney in male and female rats

BackgroundThis study was undertaken to investigate, the effect of 6 weeks treatment with acetaminophen (AAP) and fluoride (F), administered either separately or together, on nitric oxide generation, lipid and protein peroxidation, total antioxidant status and level of reduced glutathione in the liver and kidney of male and female Wistar Han rats. Also, the influence of AAP on F excretion in urine was determined.MethodsThirty adult male and female rats were divided into five equal groups of six each: (I) controls drinking tap water; (II) controls drinking tap water and receiving 1 ml of tap water intragastrically; (III) animals receiving 12 mg F/L in drinking water; (IV) animals receiving 150 mg AAP/kg b.w./day; (V) animals receiving 12 mg F/L in drinking water and 150 mg AAP/kg b.w./day.ResultsF and AAP given separately and both together enhanced oxidative and nitrosative stress in investigated tissues. No gender differences were observed in oxidative/nitrosative stress parameters during treatment with F and/or AAP. Interestingly, the combined exposure to F and AAP resulted in an enhancement of oxidative/nitrosative stress in kidney of male and female rats compared to the group treated separately with F and AAP. No additive effect in the measured parameters in the liver during co-exposure to both xenobiotics was noticed.ConclusionsAs expected, the urinary F excretion increased in an exposure time-dependent manner in rats receiving F or a combination of F and AAP. The study also showed that AAP significantly decreased urinary F.     

Oxidative stress induced by microcystin–LR on PLHC-1 fish cell line

Increasing evidences suggest that oxidative stress may play a significant role in microcystins (MCs) toxicity not only in mammals, but also in fish. In this regard, many in vivo studies have been performed but little is still known about the alteration of oxidative stress biomarkers on fish cell lines so far. In this study, the toxic effects of MC–LR were investigated in the fish cell line PLHC-1, derived from a hepatocellular carninoma of the topminnow Poeciliosis lucida, after 48 h of exposure. The different response of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST), as well as lipid peroxidation (LPO) as a biomarker of oxygen-mediated toxicity, were assessed in PLHC-1 cells. The increases in the antioxidant enzymatic activities (SOD, GPx, and GST) as well as in LPO values observed evidenced the oxidative stress induced by MC–LR exposure. Moreover, the enhancements of these enzymes could suggest an adaptative response to combat oxidative injure induced by MC–LR, confirming that this mechanism is involved in the damage induced by MCs on fish cells.     

Astaxanthin pretreatment attenuates acetaminophen-induced liver injury in mice

BackgroundAcetaminophen (APAP) is a conventional drug widely used in the clinic because of its antipyretic-analgesic effects. However, accidental or intentional APAP overdoses induce liver injury and even acute liver failure (ALF). Astaxanthin (ASX) is the strongest antioxidant in nature that shows preventive and therapeutic properties, such as ocular protection, anti-tumor, anti-diabetes, anti-inflammatory, and immunomodulatory effects. The aim of present study was to determine whether ASX pretreatment provides protection against APAP-induced liver failure.MethodsMale C57BL/6 mice were randomly divided into 7 groups, including control, oil, ASX (30 mg/kg or 60 mg/kg), APAP and APAP + ASX (30 mg/kg or 60 mg/kg) groups. Saline, olive oil and ASX were administered for 14 days. The APAP and APAP + ASX groups were given a peritoneal injection of 700 mg/kg or 300 mg/kg APAP to determine the 5-day survival rate and for further observation, respectively. Blood and liver samples were collected to detect alanine transaminase (ALT), aspartate transaminase (AST), inflammation, oxidative stress and antioxidant systems, and to observe histopathologic changes and key proteins in the mitogen-activated protein kinase (MAPK) family.ResultsASX pretreatment before APAP increased the 5-day survival rate in a dose-dependent manner and reduced the ALT, AST, hepatic necrosis, reactive oxygen species (ROS) generation, lipid peroxidation (LPO), oxidative stress and pro-inflammatory factors. ASX protected against APAP toxicity by inhibiting the depletion of glutathione (GSH) and superoxide dismutase (SOD). Administration of ASX did not change the expression of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and P38. However, phosphorylation of JNK, ERK and P38 was reduced, consistent with the level of tumor necrosis factor alpha (TNF-α) and TNF receptor-associated factor 2 (TRAF2).ConclusionASX provided protection for the liver against APAP hepatotoxicity by alleviating hepatocyte necrosis, blocking ROS generation, inhibiting oxidative stress, and reducing apoptosis by inhibiting the TNF-α-mediated JNK signal pathway and by phosphorylation of ERK and P38, which made sense in preventing and treating liver damage.     

In vitro toxicological properties of thymoquinone

Nigella sativa has been traditionally used for the treatment of inflammations, liver disorders, and arthritis. Experimentally, it has been demonstrated that N. sativa extracts and the main constituent of their volatile oil, thymoquinone, possess antioxidant, anti-inflammatory and hepato-protective properties.To further evaluate the toxicological properties in a metabolically competent cellular system, thymoquinone was applied to primary rat hepatocyte cultures, and both cyto- and genotoxic effects were tested. Mitotic indices and the rates of apoptoses and necroses were determined as endpoints of cytotoxicity, while chromosomal aberrations and micronucleated cells served as endpoints of genotoxicity.In this approach thymoquinone demonstrated cyto- and genotoxic effects in a concentration dependent manner: it induced significant anti-proliferative effects at 20 μM and acute cytotoxicity at higher concentrations. Thymoquinone significantly increased the rates of necrotic cells at concentrations between 2.5 and 20 μM. Furthermore, it induced significant genotoxicity at concentrations ?1.25 μM. These observations support the previous finding that thymoquinone causes glutathione depletion and liver damage, but contradict the reports indicating antioxidant and anti-clastogenic effects. Thymoquinone might be metabolised to reactive species and increase oxidative stress, which contributes to the depletion of antioxidant enzymes and damage to DNA in hepatocytes treated with high thymoquinone concentrations.