Effect of amlodipine,lisinopril and allopurinol on acetaminophen-induced hepatotoxicity in rats

BackgroundExposure to chemotherapeutic agents such as acetaminophen may lead to serious liver injury. Calcium deregulation, angiotensin II production and xanthine oxidase activity are suggested to play mechanistic roles in such injury.ObjectiveThis study evaluates the possible protective effects of the calcium channel blocker amlodipine, the angiotensin converting enzyme inhibitor lisinopril, and the xanthine oxidase inhibitor allopurinol against experimental acetaminophen-induced hepatotoxicity, aiming to understand its underlying hepatotoxic mechanisms.Material and methodsAnimals were allocated into a normal control group, a acetaminophen hepatotoxicity control group (receiving a single oral dose of acetaminophen; 750 mg/kg/day), and four treatment groups receive N-acetylcysteine (300 mg/kg/day; a reference standard), amlodipine (10 mg/kg/day), lisinopril (20 mg/kg/day) and allopurinol (50 mg/kg/day) orally for 14 consecutive days prior to acetaminophen administration. Evaluation of hepatotoxicity was performed by the assessment of hepatocyte integrity markers (serum transaminases), oxidative stress markers (hepatic malondialdehyde, glutathione and catalase), and inflammatory markers (hepatic myeloperoxidase and nitrate/nitrite), in addition to a histopathological study.ResultsRats pre-treated with amlodipine, lisinopril or allopurinol showed significantly lower serum transaminases, significantly lower hepatic malondialdehyde, myeloperoxidase and nitrate/nitrite, as well as significantly higher hepatic glutathione and catalase levels, compared with acetaminophen control rats. Serum transaminases were normalized in the lisinopril treatment group, while hepatic myeloperoxidase was normalized in the all treatment groups. Histopathological evaluation strongly supported the results of biochemical estimations.ConclusionAmlodipine, lisinopril or allopurinol can protect against acetaminophen-induced hepatotoxicity, showing mechanistic roles of calcium channels, angiotensin converting enzyme and xanthine oxidase enzyme in the pathogenesis of hepatotoxicity induced by acetaminophen.     

Glutathione S-transferase A1 (GSTA1) release,an early indicator of acute hepatic injury in mice

Three acute hepatic injury models (a CCl₄-induced model, APAP-induced model and ethanol-induced model) in mice were used to study the importance of GSTA1 in acute hepatic injury by comparison with a standard enzyme marker, alanine aminotransferase (ALT). GSTA1 release was demonstrated to be an earlier and more sensitive indicator of hepatotoxicity than was ALT. Significant increases in GSTA1 were detected at 2 h after CCl₄ exposure, while ALT was undetected at this time. GSTA1 was also a more sensitive indicator of hepatotoxicity than ALT after 6 h. In the APAP and ethanol models, GSTA1 was markedly increased earlier than ALT, at 2 h post exposure. The release of GSTA1 was significantly increased at a dose of 12.5 mg/kg (CCl₄ model), 100 mg/kg (APAP model) and 10 ml/kg (ethanol model), the lowest exposure concentration for each model. In contrast, AST release was not statistically significant. These results suggest that GSTA1 can be detected at low concentrations during the early stages of acute hepatic injury and that GSTA1 is a more sensitive and more accurate indicator than ALT.     

Protective effect of arabic gum against acetaminophen-induced hepatotoxicity in mice

Overdose of acetaminophen, a widely used analgesic drug, can result in severe hepatotoxicity and is often fatal. This study was undertaken to examine the effects of arabic gum (AG), which is commonly used in processed foods, on acetaminophen-induced hepatotoxicity in mice. Mice were given arabic gum orally (100 g l(-1)) 5 days before a hepatotoxic dose of acetaminophen (500 mg kg(-1)) intraperitoneally. Arabic gum administration dramatically reduced acetaminophen-induced hepatotoxicity as evidenced by reduced serum alanine (ALT) and aspartate aminotransferase (AST) activities. Acetaminophen-induced hepatic lipid peroxidation was reduced significantly by arabic gum pretreatment. The protection offered by arabic gum does not appear to be caused by a decrease in the formation of toxic acetaminophen metabolites, which consumes glutathione, because arabic gum did not alter acetaminophen-induced hepatic glutathione depletion. Acetaminophen increased nitric oxide synthesis as measured by serum nitrate plus nitrite at 4 and 6 h after administration and arabic gum pretreatment significantly reduced their formation. In conclusion, arabic gum is effective in protecting mice against acetaminophen-induced hepatotoxicity. This protection may involve the reduction of oxidative stress.     

Multi-targeted protection of acetaminophen-induced hepatotoxicity in mice by tannic acid

Tannic acid (TA) is the polyphenol that has beneficial health effects against oxidative stress. However, the hepatoprotective effects of TA are still relatively unknown. In the present study, we evaluated the effects of TA on an acetaminophen (APAP)-induced hepatotoxicity model, which was established by administration of 400 mg/kg of APAP. The levels of alanine transferase (ALT), aspartate transferase (AST), dendothelin-1 (ET-1), nitric oxide (NO) and malondialdehyde (MDA) in the APAP-induced hepatotoxicity mice were significantly increased (up to ~ 200%), while their levels were reduced by pretreatment with TA (25 and 50 mg/kg) (P < 0.05). The activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in the APAP-induced hepatotoxicity mice were significantly reduced (lower to ~ 65%), while their activities were increased by pretreatment with TA (25 and 50 mg/kg) (P < 0.05). In addition, pretreatment with oral TA (25 and 50 mg/kg) for 3 days before the APAP administration dose-dependently ameliorated changes in hepatic histopathology, suppressed overexpression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), c-fos, c-jun, NF-κB (p65) and caspase-3 (all P < 0.05), downregulated bax and upregulated bcl-2, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) (all P < 0.05) in the liver. These results indicate that TA exhibits significant hepatoprotective effects against APAP-induced hepatotoxicity and suggest that the hepatoprotective mechanisms of TA may be related to anti-oxidation, anti-inflammation and anti-apoptosis.     

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.     

Effect of astaxanthin on hepatocellular injury following ischemia/reperfusion

This study investigated the effect of astaxanthin (ASX; 3,3-dihydroxybeta, beta-carotene-4,4-dione), a water-dispersible synthetic carotenoid, on liver ischemia–reperfusion (IR) injury. Astaxanthin (5 mg/kg/day) or olive oil was administered to rats via intragastric intubation for 14 consecutive days before the induction of hepatic IR. On the 15th day, blood vessels supplying the median and left lateral hepatic lobes were occluded with an arterial clamp for 60 min, followed by 60 min reperfusion. At the end of the experimental period, blood samples were obtained from the right ventricule to determine plasma alanine aminotransferase (ALT) and xanthine oxidase (XO) activities and animals were sacrificed to obtain samples of nonischemic and postischemic liver tissue. The effects of ASX on IR injury were evaluated by assessing hepatic ultrastructure via transmission electron microscopy and by histopathological scoring. Hepatic conversion of xanthine dehygrogenase (XDH) to XO, total GSH and protein carbonyl levels were also measured as markers of oxidative stress. Expression of NOS2 was determined by immunohistochemistry and Western blot analysis while nitrate/nitrite levels were measured via spectral analysis. Total histopathological scoring of cellular damage was significantly decreased in hepatic IR injury following ASX treatment. Electron microscopy of postischemic tissue demonstrated parenchymal cell damage, swelling of mitochondria, disarrangement of rough endoplasmatic reticulum which was also partially reduced by ASX treatment. Astaxanthine treatment significantly decreased hepatic conversion of XDH to XO and tissue protein carbonyl levels following IR injury. The current results suggest that the mechanisms of action by which ASX reduces IR damage may include antioxidant protection against oxidative injury.     

Thymoquinone alleviates thioacetamide-induced hepatic fibrosis and inflammation by activating LKB1–AMPK signaling pathway in mice

The current study was conducted to investigate the anti-fibrotic effect and its possible underlying mechanisms of thymoquinone (TQ) against hepatic fibrosis in vivo. TQ is the major active compound derived from the medicinal Nigella sativa. Liver fibrosis was induced in male Kunming mice by intraperitoneal injections of thioacetamide (TAA, 200 mg/kg). Mice were treated concurrently with TAA alone or TAA plus TQ (20 mg/kg or 40 mg/kg) given daily by oral gavage. Our data demonstrated that TQ treatment obviously reversed liver tissue damage compared with TAA alone group, characterized by less inflammatory infiltration and accumulation of extracellular matrix (ECM) proteins. TQ significantly attenuated TAA-induced liver fibrosis, accompanied by reduced protein and mRNA expression of α-smooth muscle actin (α-SMA), collagen-І and tissue inhibitor of metalloproteinase-1 (TIMP-1). TQ downregulated the expression of toll-like receptor 4 (TLR4) and remarkably decreased proinflammatory cytokine levels as well. TQ also significantly inhibited phosphatidylinositol 3-kinase (PI3K) phosphorylation. Furthermore, TQ enhanced the phosphorylation adenosine monophosphate-activated protein kinase (AMPK) and liver kinase B (LKB)-1. In conclusion, TQ may reduce ECM accumulation, and it may be at least regulated by phosphorylation of AMPK signaling pathways, suggesting that TQ may be a potential candidate for the therapy of hepatic fibrosis.     

Chlorpromazine-induced hepatotoxicity during inflammation is mediated by TIRAP-dependent signaling pathway in mice

Inflammation is a major component of idiosyncratic adverse drug reactions (IADRs). To understand the molecular mechanism of inflammation-mediated IADRs, we determined the role of the Toll-like receptor (TLR) signaling pathway in idiosyncratic hepatotoxicity of the anti-psychotic drug, chlorpromazine (CPZ). Activation of TLRs recruits the first adaptor protein, Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP) to the TIR domain of TLRs leading to the activation of the downstream kinase, c-Jun-N-terminal kinase (JNK). Prolonged activation of JNK leads to cell-death. We hypothesized that activation of TLR2 by lipoteichoic acid (LTA) or TLR4 by lipopolysaccharide (LPS) will augment the hepatotoxicity of CPZ by TIRAP-dependent mechanism involving prolonged activation of JNK. Adult male C57BL/6, TIRAP^+/+ and TIRAP^?/? mice were pretreated with saline, LPS (2 mg/kg) or LTA (6 mg/kg) for 30 min or 16 h followed by CPZ (5 mg/kg) or saline (vehicle) up to 24 h. We found that treatment of mice with CPZ in presence of LPS or LTA leads to ~ 3–4 fold increase in serum ALT levels, a marked reduction in hepatic glycogen content, significant induction of serum tumor necrosis factor (TNF) α and prolonged JNK activation, compared to LPS or LTA alone. Similar results were observed in TIRAP^+/+ mice, whereas the effects of LPS or LTA on CPZ-induced hepatotoxicity were attenuated in TIRAP^?/? mice. For the first time, we show that inflammation-mediated hepatotoxicity of CPZ is dependent on TIRAP, and involves prolonged JNK activation in vivo. Thus, TIRAP-dependent pathways may be targeted to predict and prevent inflammation-mediated IADRs.     

The Th1/Th2 paradigm in lambda cyhalothrin-induced spleen toxicity: The role of thymoquinone

This study investigates the retrofitted role of thymoquinone (TQ) in the Th1/Th2 paradigm imbalance in lambda-cyhalothrin (LCT) treated rats. Four groups of male Wistar rats were formed: Group I served as control. Group II received 5 mg TQ/(kg bw) daily. Group III received 0.6 mg LCT/(kg bw). Group IV was treated with TQ and LCT. All treatments were given orally for 10 weeks. The LCT-treated group elicited a significant increase in MDA and NO levels with up-regulation of NF-κB/p65 and pro-inflammatory genes expression and their levels. Meanwhile, GSH and immunoglobulins concentrations were markedly decreased concomitant with lessening the activities of antioxidant enzymes and anti-inflammatory cytokine genes mRNA levels. The co-administration of TQ and LCT improved the altered antioxidant enzymes activities and concentration of cytokines with attenuation of NF-κB/p65 mRNA. These data support the antioxidant role of TQ in the Th1/Th2 imbalance paradigm during LCT toxicity.     

Preventive effect of γ-glutamylcysteinylethyl ester on carbon tetrachloride-induced hepatic triglyceride accumulation in mice

The effect of γ-glutamylcysteinylethyl ester (γ-GCE), which is a precursor of reduced glutathione (GSH), on carbon tetrachloride (CCl₄)-induced hepatic triglyceride (TG) accumulation in mice was investigated in comparison with that of GSH. Administration of γ-GCE (160 μmol/kg), but not GSH (160 μmol/kg), to mice at 3 h after CCl₄ injection (1 ml/kg, i.p.) significantly attenuated an increase in hepatic TG concentration at 6, 12, and 24 h after the CCl₄ injection. A decrease in hepatic GSH concentration after the CCl₄ injection was significantly diminished by the γ-GCE administration, but not by the GSH administration. The correlation coefficient between hepatic TG concentration and hepatic GSH concentration was −0.627 (P<0.001) when the results of all mice were grouped together. These results indicate that γ-GCE can attenuate CCl₄-induced hepatic TG accumulation in mice through the maintenance of hepatic GSH level.     

Acute and subchronic toxicological evaluation of Mequindox in Wistar rats

We studied an acute and subchronic oral toxicity of Mequindox (MEQ), a quinoxaline 1,4-dioxide antimicrobial promoter, in Wistar rats according to OECD guidelines. For acute toxicity study, single doses of MEQ at 175, 550 and 2000 mg/kg b.w. were administered to rats by oral gavage. The calculated LD₅₀ was 550 mg/kg b.w. In subchronic study, rats were fed diets containing 0, 55, 110 or 275 mg MEQ/kg. There was a reduction in body weight of rats fed 275 mg MEQ/kg diet. At 90 days autopsy, a significant decrease in the kidney weight was observed in males while an increase in relative liver and adrenal weights were observed in females fed 275 mg MEQ/kg diet. There was a significant increased in alanineaminotransferase (ALT) and malondialdehyde (MDA) concentrations in males, superoxide dismutase (SOD) activities in females, and aspartateaminotransferase (AST) levels in serum of both genders fed 275 mg MEQ/kg diet. Other toxic effects of 275 mg MEQ/kg diet included significant decrease in sodium and significant increase in potassium concentrations in serum in both genders. We may conclude that MEQ can induce hepatic and adrenal histological changes as well as leaking of different serum constituents in Wistar rats.     

Protective effect of nimesulide against hepatic ischemia/reperfusion injury in rats: Effects on oxidant/antioxidants,DNA mutation and COX-1/COX-2 levels

BackgroundNimesulide is a pharmacological agent and selective COX-2 inhibitor. It has anti-inflammatory, analgesic and antipyretic properties. The purpose of this study was to investigate the effect of nimesulide on oxidant/antioxidant, DNA mutation and COX-1/COX-2 activities in rat liver tissue with induced ischemia/reperfusion (I/R).MethodsBefore the experiment, rats were divided into four groups; liver ischemia/reperfusion (LIR), 50 mg/kg nimesulide + liver ischemia/reperfusion (NLIR50), 100 mg/kg nimesulide + liver ischemia/reperfusion (NLIR100) and a control group to be given a sham operation (SG). Malondialdehyde (MDA), total glutathione (GSH) levels and myeloperoxidase (MPO), COX-1/COX-2 enzyme activities and DNA damage product level results from liver tissues and serum AST and ALT levels were determined. The data obtained were compared with the results from the liver ischemia/reperfusion and sham operation groups.ResultsMDA levels, MPO and COX-2 activities and products of DNA injury were significantly lower in the groups given nimesulide, and particularly the NLIR100 group, compared to the LIR group (p < 0.05), while tGSH levels were significantly higher (p < 0.05). There was no significant difference between the NLIR50 and NLIR100 groups and the LIR group in terms of COX-1 levels (p > 0.05). AST and ALT levels were significantly lower in the other groups compared to the LIR group (p < 0.05).ConclusionsNimesulide at 100 mg/kg prevented oxidative liver damage induced with I/R significantly better than at a dose of 50 mg/kg. These experimental findings indicate that nimesulide may be useful in the treatment of hepatic I/R damage.     

Antioxidant activity and hepatoprotective property of leaf extracts of Boerhaavia diffusa Linn against acetaminophen-induced liver damage in rats

Extracts of Boerhaavia diffusa leaves were evaluated for antioxidant and hepatoprotective properties in the acetaminophen-induced liver damage model. Antioxidative evaluation of ethanolic extract gave total phenolic content, total flavonoid content, vitamin C content and vitamin E content and the levels of selenium and zinc as 6.6 ± 0.2 mg/g tannic acid equivalent, 0.092 ± 0.003 mg/g quercetin equivalent, 0.21 ± 0.03 mg/g, 0.054 ± 0.002 mg/g, 0.52 ± 0.05 ppm and 9.28 ± 0.16 ppm, respectively. The DPPH scavenging capacity and the reductive potential were 78.32 ± 2.41% and 0.65 ± 0.02 mg/g ascorbic acid, respectively. Pretreatment with aqueous and ethanolic extracts decreased the activities of alkaline phosphatase, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, and the level of bilirubin in the serum that were elevated by acetaminophen. The two extracts also ameliorated the elevation in the activities of the enzymes in the liver. Acetaminophen intoxication led to reduction in serum and liver albumin levels which were not significantly increased by pretreatment with the extracts. The extracts also protected against acetaminophen induced lipid peroxidation. These results indicated that leaf extracts from B. diffusa possess hepatoprotective property against acetaminophen-induced liver damage which may be mediated through augmentation of antioxidant defenses.     

Attenuation of uremia by orally feeding alpha-lipoic acid on acetaminophen induced uremic rats

Uremia means excess nitrogenous waste products in the blood & their toxic effects. An acute acetaminophen (paracetamol, N-acetyl p-aminophenol; APAP) overdose may result into potentially fatal hepatic and renal necrosis in humans and experimental animals. The aims of this present study were to investigate the protective effect of alpha-lipoic acid (ALA) on oxidative stress & uremia on male albino rats induced by acetaminophen. The study was performed by 24 albino male Wister strain rats which were randomly divided into four groups: Group I, control – receives normal food and water, Groups II, III & IV receive acetaminophen interperitoneally at the dose of 500 mg/kg/day for 10 days, from 11th day Groups III & IV were treated with ALA at the dose of 5 mg & 10 mg/100 g/day for 15 days, respectively. After 25 days of treatment, it was observed that there was a significant increase in plasma urea, creatinine, sodium and malondialdehyde (MDA) levels (p < 0.05) but a significant decrease in super oxide dismutase (SOD) & catalase activity & potassium level in uremic group is compared with control group & there was a significant increase in SOD & catalase (p < 0.05) & a significant decrease in serum urea, creatinine & Na and MDA (p < 0.05) in Group III & Group IV is compared with Group II & significant changes were observed in high ALA dose group. In conclusion it was observed that the ALA has nephroprotective activities by biochemical observations against acetaminophen induced uremic rats.     

The inhibition of inducible nitric oxide synthase and oxidative stress by agmatine attenuates vascular dysfunction in rat acute endotoxemic model

Vascular dysfunction leading to hypotension is a major complication in patients with septic shock. Inducible nitric oxide synthase (iNOS) together with oxidative stress play an important role in development of vascular dysfunction in sepsis. Searching for an endogenous, safe and yet effective remedy was the chief goal for this study. The current study investigated the effect of agmatine (AGM), an endogenous metabolite of l-arginine, on sepsis-induced vascular dysfunction induced by lipopolysaccharides (LPS) in rats. AGM pretreatment (10 mg/kg, i.v.) 1 h before LPS (5 mg/kg, i.v.) prevented the LPS-induced mortality and elevations in serum creatine kinase-MB isoenzyme (CK-MB) activity, lactate dehydrogenase (LDH) activity, C-reactive protein (CRP) level and total nitrite/nitrate (NOx) level after 24 h from LPS injection. The elevation in aortic lipid peroxidation illustrated by increased malondialdehyde (MDA) content and the decrease in aortic glutathione (GSH) and superoxide dismutase (SOD) were also ameliorated by AGM. Additionally, AGM prevented LPS-induced elevation in mRNA expression of iNOS, while endothelial NOS (eNOS) mRNA was not affected. Furthermore AGM prevented the impaired aortic contraction to KCl and phenylephrine (PE) and endothelium-dependent relaxation to acetylcholine (ACh) without affecting endothelium-independent relaxation to sodium nitroprusside (SNP). In conclusion: AGM may represent a potential endogenous therapeutic candidate for sepsis-induced vascular dysfunction through its inhibiting effect on iNOS expression and oxidative stress.     

Effect of nifedipine,verapamil, diltiazem and trifluoperazine on acetaminophen toxicity in mice

The hepatotoxicity of acetaminophen overdose depends on the metabolic activation to a toxic reactive metabolite by the hepatic mixed function oxidases. There is evidence that an increase in cytosolic Ca²⁺ is involved in acetaminophen hepatotoxicity. The effects of the Ca²⁺-antagonists nifedipine (NF), verapamil (V), diltiazem (DL) and of the calmodulin antagonist trifluoperazine (TFP) on the activity of some drug-metabolizing enzyme systems, lipid peroxidation and acute acetaminophen toxicity were studied in male albino mice. No changes in the drug-metabolizing enzyme activities studies and in the cytochrome P-450 and b₅ contents were observed 1 h after oral administration of V (20 mg/kg), DL (70 mg/kg) and TFP (3 mg/kg). NF (50 mg/kg) increased cytochrome P-450 content, NADPH-cytochrome c reductase and ethylmorphine-N-demethylase activities. DL and TFP significantly decreased lipid peroxidation. NF, V, DL and TFP administered 1 h before acetaminophen (700 mg/kg orally) increased the mean survival time of animals. A large increase of serum aspartate aminotransferase (AST), and liver weight and depletion of liver reduced glutathione (GSH) occurred in animals receiving toxic acetaminophen dose. NF, V and DL prevented and TFP decreased the acetaminophen-induced hepatic damage measured both by plasma AST and by liver weight. NF, V, DL and TFP changed neither the hepatic GSH level nor the GSH depletion provoked by the toxic dose of acetaminophen. This suggests that V, DL and TFP do not influence the amount of the acetaminophen toxic metabolite formed in the liver. The possible mechanism of the protective effect of NF, V, DL and TFP on the acetaminophen-induced toxicity is discussed.     

Diosgenin down-regulates NF-κB p65/p50 and p38MAPK pathways and attenuates acute lung injury induced by lipopolysaccharide in mice

Diosgenin (Dio), a major active component of steroidal sapogenin of the traditional Chinese herb Dioscorea zingiberensis C.H.Wright, shows various activities including anti-inflammatory, anti-thrombotic activities, anti-cancer properties etc. In the present study, we found that diosgenin significantly suppressed the phosphorylation of lung NF-κB p50/p65 and MAPK/p38 in lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice, when given orally at doses of 0.1, 1.0 and 10 mg/kg 1 h prior to LPS challenge (30 mg/kg, intravenous injection). Moreover, diosgenin attenuated the lung histopathological changes such as pulmonary edema, coagulation and infiltration of inflammatory cells. In addition, diosgenin significantly decreased the lung wet to dry weight (W/D) ratio and nitrite/nitrate content at three doses, and also markedly inhibited LPS-induced body temperature decrease and nitrite/nitrate elevation in plasma. Besides, diosgenin could significantly suppress activation of NF-κB p65/p50, p38 and expression of inducible nitric oxide synthase (iNOS) in LPS-induced THP-1 cells. Our findings indicate the potential application of diosgenin for ALI treatment.     

Alleviation of hepatic injury by chrysin in cisplatin administered rats: Probable role of oxidative and inflammatory markers

BackgroundCisplatin is an effective and extensively used chemotherapeutic agent to treat range of malignancies, but its therapeutic use is limited because of dose-dependent nephrotoxicity and hepatotoxicity. Several published reports advocate that supplementation with antioxidant can influence cisplatin induced hepatic damage.MethodIn the present study the Wistar rats were subjected to concurrent prophylactic oral treatment of chrysin (25 and 50 mg/kg b.wt.) against the hepatotoxicity induced by intraperitoneal administration of cisplatin (7.5 mg/kg b.wt.). Efficacy of chrysin against the hepatotoxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, histopathological changes and expression levels of molecular markers of inflammation.ResultsChrysin ameliorated cisplatin-induced lipid peroxidation, xanthine oxidase activity, glutathione depletion, decrease in antioxidant (catalase, glutathione reductase, superoxide dismutase, glutathione peroxidase and glucose-6 phosphate dehydrogenase) and phase-II detoxifying (glutathione-S-transferase and quinone reductase) enzyme activities. Chrysin also attenuated expression of COX-2, iNOS and levels of NFκB and TNF-α, and hepatic tissue damage which were induced by cisplatin. Histological findings further supported the protective effects of chrysin against cisplatin-induced hepatic damage.ConclusionThe results of the present study demonstrate that oxidative stress and inflammation are closely associated with cisplatin-induced toxicity and chrysin shows the protective efficacy against cisplatin-induced hepatotoxicity possibly via attenuating the oxidative stress and inflammatory response.     

Thymoquinone attenuates liver fibrosis via PI3K and TLR4 signaling pathways in activated hepatic stellate cells

Thymoquinone (TQ) is the major active compound derived from the medicinal Nigella sativa. In the present study, we investigated the anti-fibrotic mechanism of TQ in lipopolysaccharide (LPS)-activated rat hepatic stellate cells line, T-HSC/Cl-6. T-HSC/Cl-6 cells were treated with TQ (3.125, 6.25 and 12.5 μM) prior to LPS (1 μg/ml). Our data demonstrated that TQ effectively decreased activated T-HSC/Cl-6 cell viability. TQ significantly attenuated the expression of CD14 and Toll-like receptor 4 (TLR4). TQ also significantly inhibited phosphatidylinositol 3-kinase (PI3K) and serine/threonine kinase-protein kinase B (Akt) phosphorylation. The expression of α-SMA and collagen-I were significantly decreased by TQ. Furthermore, TQ decreased X linked inhibitor of apoptosis (XIAP) and cellular FLIP (c-FLIP_L) expression, which are related with the regulation of apoptosis. Furthermore, TQ significantly increased the survival against LPS challenge in d-galactosamine (d-GlaN)-sensitized mice, and decreased the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which were in line with in vitro results. Our data demonstrated that TQ attenuates liver fibrosis partially via blocking TLR4 expression and PI3K phosphorylation on the activated HSCs. Therefore, TQ may be a potential candidate for the therapy of hepatic fibrosis.     

The protective potential of metformin against acetaminophen-induced hepatotoxicity in BALB/C mice

Context: Acetaminophen overdose is regarded to a common cause of acute liver failure. The hepatotoxicity leads to mitochondrial oxidative stress and subsequent necrotic hepatocellular death.

Objective: This study examines the protective effect of metformin on acetaminophen-induced oxidative stress, inflammation and subsequent hepatotoxicity in mice.

Materials and methods: Male BALB/c mice were orally administered to acetaminophen (250?mg/kg/d) for a 7-day period. The mice received metformin (100 and 200?mg/kg/d, p.o.) for 21 days. To evaluate acetaminophen-induced oxidative stress, liver tissue level of malodialdehyde (MDA), end product of membrane lipid peroxidation, and activities of superoxide dismutase (SOD) and glutathione (GSH) were measured. Histological analysis and measurement of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were performed. Moreover, tissue concentrations of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), along with, C-reactive protein (CRP) were assessed.

Results: Acetaminophen caused focal hepatocyte necrosis, inflammation and fatty degeneration, as well as increased tissue levels of AST, ALT, ALP and MDA, and also decreased GSH and SOD activities. Moreover, IL-6, TNF-α and CRP levels were increased following acetaminophen hepatotoxicity. Metformin (200?mg/kg/d) significantly normalized MDA, SOD and GSH levels (p?<?0.001), and exerted a hepatoprotective effect by significant decreasing ALT, AST and ALP concentrations (p?<?0.001). The tissue levels of IL-6, TNF-α and CRP were markedly decreased by 21-day treatment with metformin (200?mg/kg/d) (p?<?0.001).

Discussion: The results suggest metformin protects hepatocytes against acute acetaminophen toxicity. Metformin is indicated to diminish oxidative stress, proinflammatory cytokines, and hepatocyte necrosis.