Acetaminophen-induced Hepatotoxicity Research Articles

Consequence of Lepidium Sativum Seeds on Flat of Biochemical Parameters in Albino Male Rats Treated with Acetaminophen

Experiment is to assess efficiency of alcoholic extract of Lepidium sativum seeds in improving erythropoietin levels and some other biological parameters against acetaminophen-induced hepatotoxicity and nephrotoxicity. The study was worked in Labs / Unive. Kufa for the period from 1/10/2021 to 1/12/2021, with a follow-up of (42) three-month-old male albino rats, their weights ranged between 215-242 g to assess the protective role of the alcoholic extract of Lepidium sativum seeds in inhibiting acetaminophen-induced hepatotoxicity and nephrotoxicity, the rats were divided into six groups with seven animals for each group. The first group, which is the control group, and they were dosed with tap water once a day, the second group, that were orally dosed with acetaminophen 1000mg\kg once, and the third group was treated with the alcoholic extract of Lepidium sativum seeds at a concentration of 250 mg/kg and an hour later was given acetaminophen 1000 mg/kg orally, while the fourth group was treated with alcoholic extract of Lepidium sativum seeds at a concentration of 500 mg/kg and an hour later they were given acetaminophen 1000 mg/kg orally, and the fifth group was treated with alcoholic extract of Lepidium sativum seeds at a concentration of 250 mg/kg orally only, and with regard to the sixth group, it was treated orally with the alcoholic extract of Lepidium sativum seeds at a concentration of 500 mg/kg only, and the treatment continued for a period of 60 days, once a day, in the morning (at half past eight). The study included evaluation of some biochemical parameters such as levels of erythropoietin hormone, iron ion, total iron binding capacity, total bilirubin, creatinine, urea, reduced and oxidized glutathione, malondialdehyde and lipid peroxide, decreasing of erythropoietin, iron ion, total iron binding capacity, reduced and oxidized glutathione, and important increase (P<0.05) in the levels of total bilirubin, creatinine, urea, malondialdehyde and lipid peroxidation in the group that was treated with the drug compared to the control group. As for the group that was given the alcoholic extract of Lepidium sativum seeds at a concentration of 250 mg/kg + acetaminophen, it did not show a protective role for this concentration against the toxic effects of the drug, as it showed important differences (P<0.05) in all parameters included in the current study compared with the control group. Contrary to above, the group that was given the alcoholic extract of Lepidium sativum seeds at a concentration of 500 mg/kg + acetaminophen did not reveal important alterations (P 0.05) in the study criteria compared with the control group. Concern to the group of rats treated with alcoholic extract of Lepidium sativum seeds concentration 250 mg/kg only, it did not give important differences in the study parameters compared with the control group, except for the level of reduced glutathione, which showed important increase (P<0.05). Finally, the group that orally dosed the alcoholic extract of Lepidium sativum seeds at a concentration of 500 mg/kg only, recorded important elevation (P<0.05) in the levels of erythropoietin hormone, iron ion, total iron binding capacity, reduced and oxidized glutathione, and in contrast important reduction (P<0.05) in the levels of total bilirubin, creatinine, urea, malondialdehyde and lipid peroxide in comparison with the control group.

ESTIMATION OF THE PROTECTIVE EFFICACY OF THE ALCOHOLIC EXTRACT OF LEPIDIUM SATIVUM SEEDS ON THE LEVEL OF ERYTHROPOIETIN AND SOME PHYSIOLOGICAL PARAMETERS OF ALBINO MALE RATS DOSED WITH ACETAMINOPHEN

The aim: The study was conducted to evaluate the protective role of the alcoholic extract of Lepidium sativum seeds in inhibiting acetaminophen-induced hepatotoxicity and nephrotoxicity.
 Study Design: With a following (42) adult albino male rats in three-month-old, whose weight ranged between (215-242) g, the animals were divided into six groups and each group had seven males, the first group was considered as control and was given tap water orally, while the second group was administrated with acetaminophen at a concentration 1000 mg/kg orally, and the third group was treated with the alcoholic extract of Lepidium sativum seeds at a concentration 250 mg/kg, and an hour later was dosed with acetaminophen 1000 mg/kg orally, as well, the fourth group was given alcoholic extract of Lepidium sativum seeds at a concentration 500 mg/kg, and after an hour, acetaminophen was given orally 1000 mg/kg, while the fifth group was subjected to the alcoholic extract of Lepidium sativum seeds at a concentration 250 mg/kg only orally, and the last group was orally treated with alcoholic extract of Lepidium sativum seeds at a concentration 500 mg/kg only, the treatment lasted for (60) days, once a day in the morning (at half past eight).
 Place and Duration of Study: The trial was carried out in the animal house belonging to the College of Education for Girls, Department of Biological Sciences \ Kufa University for the period from 1/10/2021 to 1/12/2021.
 Methodology: The study included some physiological blood parameters, hemoglobin level, erythrocyte count, packed cells volume, platelet count, total differential count of white blood cells, the biochemical study was the levels of the hormone erythropoietin.
 Results: The results showed a significant decrease (P<0.05) in hemoglobin level, erythrocyte count, packed cells volume, platelet count, lymphocyte, monocyte and eosinophil percentages, erythropoietin hormone levels, on the contrary, a notable increase (P<0.05) in the numbers of white blood cells and the percentage of neutrophils was observed in the group treated with acetaminophen compared to the control group. With regard to the group that was submitted to the Lepidium sativum seeds extract at a concentration of 250 mg/kg + acetaminophen, it did not show a preventive role for this concentration against the toxic effects of the drug, as it revealed significant differences (P<0.05) in all parameters included in the study when compared to the control group, in contrast, the group treated with Lepidium sativum seeds extract at concentration 500 mg/kg + acetaminophen did not appear significant differences in the criteria of the current study compared with the control group. As for the group of rats treated with alcoholic extract of Lepidium sativum seeds at a concentration of 250 mg/kg only, it did not exhibit remarkable differences in the study parameters in comparison to the control group, finally, the group orally dosed with alcoholic extract of Lepidium sativum seeds at a concentration 500 mg/kg only, recorded a significant increase (P<0.05) in the level of hemoglobin, numbers of erythrocyte, packed cells volume, numbers of white blood cells, percentage of lymphocytes, and levels of erythropoietin hormone in compared to the control group.
 Conclusion: the alcoholic extract of Lepidium sativum seeds at a concentration of 500 mg/kg showed a protective efficiency against the toxic impacts of acetaminophen drug, and this may be attributed to its potent antioxidant components.

Lipid-lowering, anti-inflammatory, and hepatoprotective effects of isorhamnetin on acetaminophen-induced hepatotoxicity in mice

Isorhamnetin is a hepatoprotective flavonoid molecule derived from the leaves and fruits of Hippophae rhamnoides L. However, the protective effect of isorhamnetin on acetaminophen (APAP) induced hepatotoxicity is still unknown. Thus, we aimed to investigate the lipid-lowering, anti-inflammatory, and hepatoprotective effects of isorhamnetin on APAP-induced hepatotoxicity in mice. Hepatotoxicity was induced by a single injection of APAP (300 mg/kg, intraperitoneally). Isorhamnetin (50 or 100 mg/kg, orally) and N-acetylcysteine (NAC) (200 mg/kg, orally), or vehicle control, were administered 1 h before the administration of APAP. Total antioxidant status (TAS) and total oxidative status (TOS) of liver tissue and levels of inflammatory factors (TNF-α, IL-1β, and IL-6) were analyzed by ELISA. Lipid profiles and liver function parameters were measured using an autoanalyzer. In addition, liver tissue was examined histopathologically. Isorhamnetin treatment significantly reduced the APAP-induced increase in the liver weight and liver index; it also reduced the APAP-induced increase in serum liver parameters (ALT, AST, ALP, and LDH) (p < 0.05). Isorhamnetin significantly reduced APAP-induced oxidative stress and inflammation by increasing TAS levels and decreasing TOS, TNF-α, IL-1β, and IL-6 levels (p < 0.05). Moreover, isorhamnetin treatment significantly regulated lipid profiles (TG, T-C, LDL-C, and HDL-C levels) that changed in response to APAP administration (p < 0.05). In histopathological examination, liver degeneration observed in the APAP group was significantly reduced in the NAC and isorhamnetin-treated groups (p < 0.05). This study suggests that isorhamnetin has a significant protective effect on APAP-induced hepatotoxicity in mice through its lipid-lowering, antioxidant, and anti-inflammatory effects.

Effect of Pu-erh tea on acetaminophen-induced hepatotoxicity assessed by physiological, metabolomic, and transcriptomic analyses

• PTE pretreatment ameliorated oxidative stress, inflammatory response, and apoptosis of mice caused by excess APAP. • PTE pretreatment and APAP overdose altered the metabolic profile and gene expression of liver tissues. • PTE induced tyrosine and caffeine metabolism, and alleviated hepatotoxicity induced by excess APAP. • Six DEMs and 10 DEGs were biomarkers and key genes for liver protection in high dose APAP exposure. Acetaminophen (APAP) is a painkiller that can cause hepatotoxicity if taken in excess. We investigated the effect of pu-erh tea extract (PTE) on hepatotoxicity induced by excess APAP using physiological, metabolomic, and transcriptomic analyses. PTE decreased levels of oxidative stress, inflammatory response, and apoptosis markers induced by excess APAP. And 156 metabolites and 703 genes were identified as differentially expressed metabolites and differentially expressed genes, respectively. KEGG enrichment analysis revealed that PTE and overdose of APAP altered tyrosine, caffeine, and amino acid-related metabolism. Six differentially expressed metabolites associated with these pathways have hepatoprotective effects and were upregulated by PTE pretreatment. The expression levels of 10 vital differentially expressed genes regulating these metabolites were verified by qRT-PCR. The findings confirm the beneficial role of PTE pretreatment in alleviating the hepatotoxicity caused by overdose of APAP, indicating that PTE can be used as an effective dietary supplement for the development of functional foods.

Protective Effects of Interleukin-37 Expression against Acetaminophen-Induced Hepatotoxicity in Mice.

Aim Interleukin (IL)-37 is a new anti-inflammatory cytokine of the IL-1 family. This study aimed to determine the effects of IL-37 on acetaminophen (APAP)-induced liver injury. Materials and Methods IL-37 plasmids were injected into mice via a tail vein hydrodynamics-based gene delivery. Results Our results showed that IL-37 pretreatment significantly decreased serum alanine aminotransferase and aspartate aminotransferase levels, hepatic myeloperoxidase activity, and attenuated the histological liver damage. Compared to the APAP group, IL-37 administration decreased Kupffer cells numbers in the liver of APAP-induced hepatotoxicity in mice. Furthermore, IL-37 pretreatment reduced the expression of proinflammatory cytokines including tumor necrosis factor-α, IL-6, IL-17, and nuclear factor-κB (NF-κB) in APAP-induced mice. Conclusion These results demonstrate that delivery of IL-37 plasmid can ameliorate APAP-induced liver injury by reducing proinflammatory cytokines production and preventing the activation of the NF-κB signaling pathway. IL-37 may be a promising candidate against APAP-induced liver injury.

Diacerein counteracts acetaminophen-induced hepatotoxicity in mice via targeting NLRP3/caspase-1/IL-1\u03b2 and IL-4/MCP-1 signaling pathways

The current study aims at repurposing the anti-arthritic drug diacerein (DCN) for the treatment of acetaminophen hepatotoxicity and investigating the potential underlying mechanisms. Mice were randomly divided into six groups receiving either no treatment (control group), 20 mg/kg DCN i.p, 400 mg/kg acetaminophen i.p, DCN 4 h before acetaminophen, DCN 2 h after acetaminophen, or 400 mg/kg N-acetylcysteine (NAC) i.p, 2 h after acetaminophen. Biomarkers of liver dysfunction, oxidative stress, and apoptosis were assessed. Hepatic necroinflammatory changes were evaluated along with hepatic expression of NF-κB and caspase-1. The levels of NLRP3, IL-1β, IL-4, MCP-1, and TNF-α in the liver, as well as CYP2E1 mRNA expression, were measured. Diacerein significantly reduced biomarkers of liver dysfunction, oxidative stress, hepatocyte necrosis, and infiltration of neutrophils and macrophages whether administered 4 h before or 2 h after acetaminophen. Further, the effects were comparable to those of NAC. Diacerein also counteracted acetaminophen-induced hepatocellular apoptosis by increasing Bcl-2 and decreasing Bax and caspase-3 expression levels. Moreover, DCN normalized hepatic TNF-α and significantly decreased NF-κB p65 expression. Accordingly, DCN can prevent or reverse acetaminophen hepatotoxicity in mice, suggesting potential utility as a repurposed drug for clinical treatment.

Kahweol Protects against Acetaminophen-Induced Hepatotoxicity in Mice through Inhibiting Oxidative Stress, Hepatocyte Death, and Inflammation

Acetaminophen (APAP) can cause acute liver failure, but treatment options are still limited. Kahweol is the main diterpene compound of coffee and possesses antioxidant and anti-inflammatory properties. Emerging evidence suggests that this natural diterpene exerts favorable effects on several inflammatory diseases. However, the action of kahweol on APAP toxicity has not been addressed. The purpose of this study was to explore whether kahweol has a protective activity against APAP-induced hepatotoxicity and to investigate the mechanism. Administration of kahweol reduced serum levels of liver injury indicators and ameliorated histological abnormalities in APAP-treated mice. Kahweol inhibited lipid peroxidation and nucleic acid oxidation with restoration of glutathione content and stimulation of nuclear factor erythroid-2-related factor 2-dependent cellular defense system. Hepatocyte death was also decreased by kahweol, which was associated with inhibition of endoplasmic reticulum (ER) stress. Moreover, kahweol reduced hepatic levels of inflammatory mediators, inhibited nuclear factor-κB activation, and attenuated infiltration of neutrophils and macrophages. These findings suggest that kahweol has a protective activity against APAP-induced liver injury and this effect is related to the suppression of oxidative stress, hepatocyte death, ER stress, and inflammation.

Protective Effects of Virgin Coconut Oil on Acetaminophen-Induced Hepatotoxicity in Wistar Rats

Protective Effects of Virgin Coconut Oil on Acetaminophen-Induced Hepatotoxicity in Wistar Rats

Interruption of bile acid uptake by hepatocytes after acetaminophen overdose ameliorates hepatotoxicity

Background & AimsAcetaminophen (APAP) overdose remains a frequent cause of acute liver failure, which is generally accompanied by increased levels of serum bile acids (BAs). However, the pathophysiological role of BAs remains elusive. Herein, we investigated the role of BAs in APAP-induced hepatotoxicity.MethodsWe performed intravital imaging to investigate BA transport in mice, quantified endogenous BA concentrations in the serum of mice and patients with APAP overdose, analyzed liver tissue and bile by mass spectrometry and MALDI-mass spectrometry imaging, assessed the integrity of the blood-bile barrier and the role of oxidative stress by immunostaining of tight junction proteins and intravital imaging of fluorescent markers, identified the intracellular cytotoxic concentrations of BAs, and performed interventions to block BA uptake from blood into hepatocytes.ResultsPrior to the onset of cell death, APAP overdose causes massive oxidative stress in the pericentral lobular zone, which coincided with a breach of the blood-bile barrier. Consequently, BAs leak from the bile canaliculi into the sinusoidal blood, which is then followed by their uptake into hepatocytes via the basolateral membrane, their secretion into canaliculi and repeated cycling. This, what we termed ‘futile cycling’ of BAs, led to increased intracellular BA concentrations that were high enough to cause hepatocyte death. Importantly, however, the interruption of BA re-uptake by pharmacological NTCP blockage using Myrcludex B and Oatp knockout strongly reduced APAP-induced hepatotoxicity.ConclusionsAPAP overdose induces a breach of the blood-bile barrier which leads to futile BA cycling that causes hepatocyte death. Prevention of BA cycling may represent a therapeutic option after APAP intoxication.Lay summaryOnly one drug, N-acetylcysteine, is approved for the treatment of acetaminophen overdose and it is only effective when given within ∼8 hours after ingestion. We identified a mechanism by which acetaminophen overdose causes an increase in bile acid concentrations (to above toxic thresholds) in hepatocytes. Blocking this mechanism prevented acetaminophen-induced hepatotoxicity in mice and evidence from patients suggests that this therapy may be effective for longer periods after ingestion compared to N-acetylcysteine.

The effect of nutritional status on the pharmacokinetic profile of acetaminophen

Nutritional imbalance (low protein / high fat) is a public health problem affecting many people in developing and developed nations. Such an imbalance will influence pathophysiological homeostasis in individuals and thereby considerably impact drug pharmacokinetics. It was reported that short-term fasting increases acetaminophen exposure in healthy subjects, whereas no effect was observed after a high-fat diet. These findings suggest the necessity of considering nutritional status when assessing the risk of acetaminophen-induced hepatotoxicity. Additionally, the role of nutrition status on the pharmacokinetic profile of acetaminophen (APAP) at toxic doses is either scanty or not available. With this background, we aimed to compare the effects of nutrition status on the pharmacokinetic profile of APAP at a toxic dose in three different dietary regimens like - Normal diet (ND), Low protein diet (LPD), and High-fat diet (HFD). Balb/C female mice were divided into three groups after weaning, and for the next 15 weeks, they were fed with their respective diets (ND, LPD, and HFD). After that, mice were dosed with APAP (300 mg/kg p.o), and blood sampling was done at different time intervals and centrifuged at 3000 rpm for 5 min to collect plasma samples. Plasma samples were analyzed using the HPLC method. Data analysis was done by Non-compartment analysis using Phoenix WinNonlin 8.3 software. LPD group shows higher values of Cmax, tmax, t1/2, and AUC0–4, AUC0-x values than ND and HFD groups. Both Cmax and AUC follow the pattern of drug exposure where LPD > ND > HFD. In conclusion, nutrition in the diet alters APAP pharmacokinetic profile at a toxic dose in three different diet regimes. Further study on CYP450 concentration and activity is essential to understand the pharmacokinetics difference between these dietary regimens.

Hepatoprotective effect of β-myrcene pretreatment against acetaminophen-induced liver injury.

Objective:In the present study, the hepatoprotective effects of β-myrcene (MYR) on acetaminophen-induced hepatotoxicity were investigated.Materials and Methods:A total of 40 Balb/c mice were randomly divided into five groups as follows: 1) Normal control group which received only carboxymethylcellulose (CMC), the vehicle used to dissolve acetaminophen (N-acetyl-p-aminophenol, APAP, paracetamol) and MYR; 2) APAP group which received a single dose of acetaminophen (250 mg/kg) orally on day 7; 3) Silymarin group which received 200 mg/kg/day of silymarin; and 4 and 5) pretreatment groups in which, mice were treated with 100 or 200 mg/kg/day of MYR. Liver and blood samples were collected to analyze serum aminotransferases, inflammatory response, oxidative stress markers, and histopathological insults.Results:Our results showed that MYR pretreatment attenuated liver damage and restored liver cells function and integrity as it decreased the leakage of serum aminotransferases (alanine and aspartate aminotransferases (ALT and AST, respectively)) into the blood (p<0.01). MYR treatment also reduced levels of myeloperoxidase (MPO) activity and nitric oxide (NO) (p<0.001). In addition, MYR pretreatment demonstrated significant antioxidant activity by decreasing malondialdehyde (MDA), reactive oxygen species (ROS), and reduced glutathione (GSH) levels (p<0.001). Furthermore, it restored the hepatic level of superoxide dismutase (SOD), catalase (CAT), and oxidized glutathione (GSSG) (p<0.001). Conclusion:For the first time, our results showed that MYR treatment significantly improved liver function by reducing oxidative stress and the inflammatory response induced by APAP.

Disruption of peroxisome proliferator-activated receptor α in hepatocytes protects against acetaminophen-induced liver injury by activating the IL-6/STAT3 pathway.

Background & Aims: Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor abundantly expressed in liver. PPARα activator has been previously reported to protect against acetaminophen-induced hepatotoxicity, but fenofibrate, a lipid-lowering drug that activates PPARα, has a common side-effect causing liver injury. Thus, the exact effect of liver PPARα on drug-induced liver injury remains obscure.Methods: Hepatocyte-specific Ppara knockout mice and littermate wild-type control mice were intraperitoneally injected with acetaminophen (400 mg/kg body weight). Blood and liver samples were collected at different time points. We measured phase I and II cytochrome P450 enzymes, glutathione, reactive oxygen species, cytokines including Il6, and pSTAT3 by reverse transcriptase quantitative PCR, colorimetric, immunohistochemistry analyses and Western blotting.Results: Hepatic expression of PPARα was significantly decreased in DILI patients. Disruption of the Ppara gene in hepatocytes significantly reduced acetaminophen-induced liver injury in mice. ROS production rather than the expression levels of phase I and II cytochrome P450 enzymes was reduced in hepatocyte-specific Ppara knockout mice compared to control mice after acetaminophen administration. Mechanistically, hepatocyte-specific Ppara knockout mice had upregulated activation of the hepatoprotective pathway IL-6/STAT3 compared to wild-type mice, as evidenced by hepatic Il6 mRNA levels, hepatic protein levels of STAT3 and phosphorylated STAT3 were much higher in hepatocyte-specific Ppara knockout mice than in wild-type mice post acetaminophen injection.Conclusions: Hepatocyte-specific disruption of the Ppara gene protects against acetaminophen-induced liver injury by reducing oxidative stress and upregulating the hepatoprotective IL-6/STAT3 signaling pathway.

Naringin regulates mitochondrial dynamics to protect against acetaminophen-induced hepatotoxicity by activating the AMPK/Nrf2 signaling pathway in vitro.

Naringin (Nar) has been reported to exert potential hepatoprotective effects against acetaminophen (APAP)-induced injury. Mitochondrial dysfunction plays an important role in APAP-induced liver injury. However, the protective mechanism of Nar against mitochondrial damage has not been elucidated. Therefore, the aim of this study was to investigate the hepatoprotective effects of Nar against APAP and the possible mechanisms of actions. Primary rat hepatocytes and HepG2 cells were utilized to establish an in vitro model of APAP-induced hepatotoxicity. The effect of APAP and Nar on cell viability was evaluated by a CCK8 assay and detection of the concentrations of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase. The cellular concentrations of biomarkers of oxidative stress were measured by ELISA. The mRNA expression levels of APAP-related phase II enzymes were determined by real-time PCR. The protein levels of Nrf2, phospho (p)-AMPK/AMPK, and biomarkers of mitochondrial dynamics were determined by western blot analysis. The mitochondrial membrane potential (MMP) was measured by high-content analysis and confocal microscopy. JC-1 staining was performed to evaluate mitochondrial depolarization. Nar pretreatment notably prevented the marked APAP-induced hepatocyte injury, increases in oxidative stress marker expression, reductions in the expression of phase II enzymes, significant loss of MMP, mitochondrial depolarization, and mitochondrial fission in vitro. In conclusion, Nar alleviated APAP-induced hepatocyte and mitochondrial injury by activating the AMPK/Nrf2 pathway to reduce oxidative stress in vitro. Applying Nar for the treatment of APAP-induced liver injury might be promising.

The Benevolent Bile: Bile Acids as Stimulants of Liver Regeneration

The Benevolent Bile: Bile Acids as Stimulants of Liver Regeneration

Hepatic SIRT6 Modulates Transcriptional Activities of FXR to Alleviate Acetaminophen-induced Hepatotoxicity

Background & AimsExcessive acetaminophen (APAP) intake causes oxidative stress and inflammation, leading to fatal hepatotoxicity; however, the mechanism remains unclear. This study aims to explore the protective effects and detailed mechanisms of sirtuin 6 (SIRT6) in the defense against APAP-induced hepatotoxicity.MethodsHepatocyte-specific SIRT6 knockout mice, farnesoid X receptor (FXR) knockout mice, and mice with genetic or pharmacological activation of SIRT6 were subjected to APAP to evaluate the critical role of SIRT6 in the pathogenesis of acute liver injury. RNA sequences were used to investigate molecular mechanisms underlying this process.ResultsHepatic SIRT6 expression was substantially reduced in the patients and mice with acute liver injury. The deletion of SIRT6 in mice and mice primary hepatocytes led to high N-acetyl-p-benzo-quinoneimine and low glutathione levels in the liver, thereby enhancing APAP overdose-induced liver injury, manifested as increased hepatic centrilobular necrosis, oxidative stress, and inflammation. Conversely, overexpression or pharmacological activation of SIRT6 enhanced glutathione and decreased N-acetyl-p-benzo-quinoneimine, thus alleviating APAP-induced hepatotoxicity via normalization of liver damage, inflammatory infiltration, and oxidative stress. Our molecular analysis revealed that FXR is regulated by SIRT6, which is associated with the pathological progression of ALI. Mechanistically, SIRT6 deacetylates FXR and elevates FXR transcriptional activity. FXR ablation in mice and mice primary hepatocytes prominently blunted SIRT6 overexpression and activation-mediated ameliorative effects. Conversely, pharmacological activation of FXR mitigated APAP-induced hepatotoxicity in SIRT6 knockout mice.ConclusionsOur current study suggests that SIRT6 plays a crucial role in APAP-induced hepatotoxicity, and pharmacological activation of SIRT6 may represent a novel therapeutic strategy for APAP overdose-induced liver injury.

In vitro analysis of synergistic effect of honey against chemically induced hepatic insult in Balb/c mice.

Human being knows honey since thousands of years for its nutritional and medicinal values. Traditional medicine systems like Ayurveda have elaborated honey as boon for health and patient care. Synergistic effect of honey was research but to a limited extend. Honey is advised with Picrorhiza kurroa for hepatic disorders or hepato-protection in Ayurveda. Here we have examined in vitro synergistic effect of honey when given with Picrorhiza kurroa in acetaminophen-induced hepatotoxicity in Balb/c mice model. We obtained Serum and liver lysate to check levels of hepatic markers, Alkaline phosphatase and Glutathione. The level of alkaline phosphatase raised while glutathione level is reduced during hepatic offence. We observed a compensation of above markers when P. Kurrua, honey and its combination were used in acetaminophen induced hepatic toxicity. We observed a better mice weight gain in combination group (Group IV) compared to control group. This study can pave a way for future research on honey as a better adjuvant for hepatotoxic drugs and other herb-drug interactions researches.

Protective Effect of Eugenol against Acetaminophen-Induced Hepatotoxicity in Human Hepatocellular Carcinoma Cells via Antioxidant, Anti-Inflammatory, and Anti-Necrotic Potency

BACKGROUND: Overdoses acetaminophen (APAP) could cause acute liver failure, even though it used is for analgesics. APAP could cause hepatotoxicity due to multiple mediators of inflammation and oxidative stress. Eugenol has been reported to have anti-inflammatory and antioxidant activity but its hepatoprotective effect has not been widely reported. AIM: The purpose of this research is to know if eugenol could protect HepG2 cells from APAP. METHODS: HepG2 that induced by APAP as hepatotoxicity cells model was treated by using eugenol at 6.25 and 25 μg/mL. The protective effects of eugenol toward hepatotoxicity were evaluated by determine tumor necrosis factor-α (TNF-α) concentration, apoptotic activity, reactive oxygen species (ROS) level, also cytochrome (CYP)2E1 and GPX gene expression. RESULTS: Eugenol at 6.25 and 25 μg/mL concentration can reduce TNF-α concentration, the apoptotic, necrotic, dead cells, and ROS level. Besides it can increase the gene expression (GPX and CYP2E1). The best hepatoprotective effect was found when using the eugenol at 25 μg/mL. CONCLUSION: Therefore, eugenol can be used to protect HepG2 cells against APAP.

Antioxidant and hepatoprotective potential of sweet basil (Ocimum basilicum L.) extract in acetaminophen-induced hepatotoxicity in rats

This research aimed to examine the effects of pre-treatment with basil extract, prepared as an infusion, on acetaminophen-induced acute liver injury in rats. In vitro analysis of total phenolic, flavonoid content, and antioxidant activity was performed by spectrophotometric methods. Effects of basil extract on oxidative stress parameters, biochemical markers of liver injury, and liver morphology were determined in an in vivo model of acetaminophen-induced liver injury in Wistar rats. Total phenolic content was 52.61 ± 1.35 mg GAE/g of DE, and flavonoid content was 0.5 ± 0.2 mg QE/g of DE. IC50 values ranged from 0.22 to 45.76 μg/ml for DPPH radical, OH radical, H2O2 and lipid peroxidation. Ascorbic acid was used as a positive control. The extract lowered the intensity of lipid peroxidation and potentiated the activity of antioxidant enzymes. In addition, serum levels of aspartate aminotransferase and alanine aminotransferase were significantly lower in basil extract-treated animals in comparison to respective controls.

Effects of Virgin Coconut Oil on Acetaminophen-Induced Hepatotoxicity in Wistar Rats

Effects of Virgin Coconut Oil on Acetaminophen-Induced Hepatotoxicity in Wistar Rats

Extract of Triticum aestivum Sprouts Suppresses Acetaminophen-Induced Hepatotoxicity in Mice by Inhibiting Oxidative Stress.

Wheat (Triticum aestivum L.) is the oldest known food crop, and many studies have reported that wheat shoots (i.e., wheatgrass) possess anti-cancer, anti-inflammatory, and antioxidant activities. However, the potentially ameliorative effect of wheat shoots on hepatotoxicity caused by high doses of N-acetyl-para-aminophenol (acetaminophen, APAP) has yet to be reported. C57BL/6 mice received daily oral TAE (100 or 200 mg/kg), positive control (silymarin 100 mg/kg), or negative control (saline vehicle) treatments for 7 days prior to intraperitoneal APAP injection. Histological, serum (ELISA), Western blotting, and quantitative PCR analyses of excised liver tissues were then performed. Pre-treatment with TAE (100 or 200 mg/kg) ameliorated APAP-induced pathological damage (i.e., hepatotoxic lesions), reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and also ameliorated APAP-induced increases in oxidative stress, thereby inhibiting oxidative liver damage and reducing the expression of inflammatory cytokines. In addition, TAE pre-treatment inhibited the expression of Cytochrome P4502E1 (CYP2E1), which is a key enzyme in the onset of APAP-induced hepatotoxicity, suppressed the expression of the target proteins regulated by the antioxidant enzyme Nrf2, and suppressed hepatocyte apoptosis. These findings suggest that TAE is an attractive therapeutic candidate that exhibits potential hepatoprotective activity by inhibiting oxidative stress, inflammation, apoptosis, and liver damage.