Acetaminophen-induced Toxicity Research Articles

Influence of Pre-treatment of Withania somnifera Root Extract and Cow Urine on Hemato-biochemical Parameters in Acetaminophen-induced Toxicity in Swiss Albino Male Mice

Background: The present study was undertaken to investigate protective activity of W. somnifera root extract (W.S.R.E.), cow urine (C.U.) and their combination against acetaminophen (APAP) induced toxicity in male mice. APAP also known as paracetamol, is a well-known drug used for its analgesic and antipyretic effects. However, outside of the therapeutic window, the toxicity may result. W.S. and C.U. are from indigenous sources of plant and animal origins, respectively with several therapeutic activities. Methods: Sixty adult swiss albino male mice were randomly divided into six groups, comprising of ten mice in each group. Group I (control group) received 2% gum acacia suspension for 14 days orally and on day 14, 0.9% NaCl (@300 mg/kg b.wt.) intraperitoneally was administered after 30 min of prior treatment of various agents. Group II, III, IV, V and VI received 2% gum acacia, silymarin (@25 mg/kg b.wt.), W.S.R.E. (@100 mg/kg b.wt.), C.U. (@7.8 mL/kg b.wt.) and W.S.R.E. (@100 mg/kg b.wt.) and C.U. (@7.8 mL/kg b.wt.) co-treatment orally for 14 days and on day 14, APAP (@300 mg/kg b.wt.) intraperitoneally was administered after 30 min of prior treatment of various agents as mentioned. On 15th day, the animals were sacrificed and samples were collected to study various hematobiochemical and growth related parameters. Result: The treatment of acetaminophen caused significant decrease in haemoglobin, total erythrocyte count whereas increase in total leucocyte and prothrombine time. There were significant (p£0.05) decreases in plasma total protein, albumin and globulin values in group II (APAP), as compared to control (group I). Treatment with W.S. +C.U attenuates these alterations. W.S.R.E., C.U. and their combination pre-treatment mildly restored the changes to normal observed following APAP exposure in mice. However, the results of co-treatment group were more pronounced as compared to individual treatment groups. Thus, it was concluded that treatment with W.S.R.E. and C.U. curtailed the toxic effect of APAP, however, co-administration of both potentiated the protective effect.

Evaluating the Nephroprotective and Hepato-protective Effects of Hypoestes rosea in Acetaminophen-Induced Toxicity in Albino Rats

The leaves of Hypoestes rosea are in use as traditional medicine in the Niger Delta areas in Nigeria and the Western part of Cameroun for the management of different ailments in children, such as anaemia, malaria, fever and other ailments. Regardless of its uses, scanty studies evaluating its organ protective effects exist. Therefore, this research study evaluates the nephroprotective and hepato-protective effects of Hypoestes rosea in acetaminophen-induced toxicity in Albino rats. The objectives of this research study are to evaluate the protective effect of Hypoestes rosea on the kidney and the liver of albino rats. Acetaminophen, which is frequently used as an analgesic and antipyretic drug at high doses, can be harmful to vital organs of the body, affecting the liver and kidneys. In this study, effects of an aqueous extract of Hypoestes rosea (AEHr) on liver function parameters and kidney function parameters of acetaminophen induced-toxicity in albino rats were evaluated using acute (15 days) and sub-chronic (30 days) duration of study and study group comprising of prophylactic (pre-treatment) and therapeutic (post-treatment) phases with six experimental groups in each phase. A total of 112 adult apparently healthy Albino rats weighing (180-220g) were used for this study, divided into six experimental groups of extract control (EC), negative control (NC), positive control (PC), AEHr100mg/kg b w., AEHr 200mg/kg b w., and AEHr 300mg/kg b w. groups each of six rats. At the end of the research study period, blood samples were collected through jugular puncture for liver and kidney function parameters. Results showed that acetaminophen-induced toxicity in albino rats caused toxicity to the kidney and toxicity to the liver, as evidenced by the raised levels of potassium, urea, creatinine and low bicarbonate from the renal function parameters and also as evidenced by significant elevation of bilirubin and liver enzymes with a significantly low total protein and albumin levels from the liver function parameters when compared with other experimental groups. Conversely, AEHr at different concentrations in a dose-dependent pattern at the different treatment phases and different duration periods were able to repair the injury to the kidney and liver caused by acetaminophen induction to normal. Consequently, the findings of this research propose that Hypoestes rosea contains active ingredients accountable for the nephroprotective and hepato-protective abilities in rats and can be recommended for more studies using higher mammals.

Protective effect of nanocurcumin on acetaminophen-induced hepatic and renal toxicities in pigeons.

In this study, the effects of nanocurcumin on acetaminophen-induced acute hepatorenal toxicity in domestic pigeons (Columba livia) were investigated. Fifteen pigeons were randomly assigned into three groups. Group I was served as a negative control group and received tap water as a placebo. Pigeons in groups II and III were administered acetaminophen at the beginning of the experiment (hr 0). Group III was further treated with nanocurcumin, at 12 hr after acetaminophen administration, being continued every 12 hr for two days. The birds were observed for clinical signs of acute drug toxicity. Blood samples were collected from the pigeons at hr 0, 12, 24 and 48 of the experiment for biochemical analysis of the serum. The results showed that acetaminophen toxicity increased the serum levels of aspartate aminotransferase, alanine aminotransferase, urea and uric acid in the pigeons. Nanocurcumin treatment of acetaminophen intoxicated pigeons attenuated increases in biomarkers of the liver and kidney functions towards control levels. Also, the consumption of nanocurcumin minimized histopathological changes in the liver and kidney. A mortality of 60.00% was seen in the acetaminophen-induced toxicity group; while, none of the birds treated with nanocurcumin died. It can be concluded that nanocurcumin alleviates the acetaminophen-induced acute toxic liver and kidney damages, which can lead to pigeon mortality.

Antimycobacterial, hepatoprotective and cytotoxicity effects of selected plant species from the Menispermaceae family

Tuberculosis, caused by Mycobacterium tuberculosis, is a worldwide disease affecting millions of people. The rise of resistant strains, coupled with toxicity of current chemotherapy, requires effective alternatives against mycobacterial infections. Some plants from the Menispermaceae family have been used to treat tuberculosis and cough related symptoms. In this study, acetone, methanol:water (4:1), dichloromethane:methanol (1:1) and hot water extracts of different plant parts of Cissampelos owariensis, Cissampelos mucronata and Tinospora fragosa were tested against M. aurum, M. bovis, M. fortuitum, M. smegmatis and M. tuberculosis using a two-fold serial microdilution assay. Cytotoxicity of the active extracts was determined against Vero and HepG2 cells. The hepatoprotective effect of the active extracts was evaluated using rifampicin and acetaminophen as toxic drugs against HepG2 cells. The hot water leaf extracts were most active with promising minimum inhibitory concentration (MIC) values of 20 and 40 µg/mL against M. smegmatis and M. fortuitum respectively. The acetone extracts of C. owariensis, C. mucronata and T. fragosa had the lowest MIC values (0.03 – 1.67 mg/mL). The root extract of C. owariensis was not toxic to Vero cells while the leaf extract was more toxic. The acetone extract of C. mucronata leaves was toxic to Vero cells but the other extracts had low toxicity. The active leaf and root extracts had protective effects on rifampicin-induced toxicity on HepG2 cells. The root extract also had a protective effect on acetaminophen-induced toxicity on HepG2 cells but the leaf extract had no protective effect. The hot water extracts of C. owariensis, C. mucronata and T. fragosa had a more protective effect on the toxin-induced cells than the acetone extracts. These results support further investigation on the bioactive compounds in these plant extracts.

Alleviation of acetaminophen-induced liver failure using silibinin nanoliposomes: An in vivo study

BackgroundAcetaminophen (Act) overdose is a known inducer of liver failure in both children and adults. Cell annihilation ensues following acetaminophen overdose and its toxic metabolites by depleting cellular GSH storage and increasing ROS levels. Silymarin extract and its major compound silibinin (SLB) possess robust antioxidant properties by inducing ROS elimination; however, low bioavailability and rapid metabolism limit their applications. Herein, we aimed at using SLB liposomes to combat acetaminophen-induced acute liver toxicity. MethodsWe have developed a SLB-lipid complex to improve SLB loading efficiency within nanoliposome by using the lipid film method. Liposomes were characterized by using DLS and TEM analysis, and the release pattern, and toxicity profile on the normal cells as well as histopathological and serum analysis were investigated to reveal relevant enzyme activities in an animal model. ResultsData demonstrated that negatively-charged SLB liposomes of 115 nm had homogeneous spherical morphology, and entrapped a considerable quantity of SLB of almost 40%. Liposomes shows a favorable release pattern and were not toxic against NIH3T3 mouse fibroblast cells. The animal study revealed that treatment of mice with SLB nanoliposomes could significantly preserve liver function as revealed by the reduced levels of ALT and AST hepatic enzymes as well as ALP in the serum. Our data indicated that intraperitoneal administration of SLB Lip could significantly reduce ALT enzyme levels (p < 0.05) compared to N-acetylcysteine, while i.v administration resulted in no significant difference compared to control animals with no treatment. ConclusionThe results of this study support the significant hepatoprotective effect of SLB nanoliposomes against acetaminophen-induced toxicity depending on the route of administration.

Evaluation of the therapeutic potential of vomit seed (Strychnos nux-vomica) homeopathic treatment in acute acetaminophen-induced toxicity

Purpose: To investigate the effect of vomit seed homeopathic drugs (14CH and 30CH) on paracetamolinduced toxicity in rats.&#x0D; Methods: Thirty-two male Wistar rats were divided into 4 groups of 8 animals each (n = 8) and treated for 12 days. During the treatment period, group (G) one (G1) which constitutes the control group received filtered water, whereas groups two (G2), three (G3), and four (G4) were gavaged with a toxic dose of paracetamol 1/4 of LD50. Next, Strychnos nux-vomica (0.5 mg/kg) homeopathic dilutions of 14CH and 30CH were administered to G3 and G4, respectively. Hematological, biochemical, and antioxidant markers were assessed.&#x0D; Results: Homeopathic drug groups, namely G3 and G4, showed significant recovery in some hematological (red blood cells count and hemoglobin concentration; p &lt; 0.01) and biochemical parameters (urea, creatinine, glutamic transaminase, and alkaline phosphatase; p &lt; 0.001). The level of malondialdehyde significantly decreased while glutathione level significantly increased in treated rats.&#x0D; Conclusion: The antioxidant and anti-hemolytic properties of vomit seeds protect against paracetamolinduced acute toxicity in rats by reducing oxidative stress, hepatotoxicity, and nephrotoxicity in rats.

Acetaminophen for the patent ductus arteriosus: has safety been adequately demonstrated?

Patent ductus arteriosus (PDA) is the most common cardiovascular condition diagnosed in premature infants. Acetaminophen was first proposed as a potential treatment for PDA in 2011. Since that time acetaminophen use among extremely preterm neonates has increased substantially. The limited available data demonstrate that acetaminophen reduces PDA without evident hepatotoxicity. These findings have led some to suggest that acetaminophen is a safe and effective therapy for PDA closure. However, the lack of apparent hepatoxicity is predictable. Acetaminophen induced cellular injury is due to CYP2E1 derived metabolites; and hepatocyte CYP2E1 expression is low in the fetal and neonatal period. Here, we review preclinical and clinical data that support the hypothesis that the lung, which expresses high levels of CYP2E1 during fetal and early postnatal development, may be particularly susceptible to acetaminophen induced toxicity. Despite these emerging data, the true potential pulmonary risks and benefits of acetaminophen for PDA closure are largely unknown. The available clinical studies in are marked by significant weakness including low sample sizes and minimal evaluation of extremely preterm infants who are typically at highest risk of pulmonary morbidity. We propose that studies interrogating mechanisms linking developmentally regulated, cell-specific CYP2E1 expression and acetaminophen-induced toxicity as well as robust assessment of pulmonary outcomes in large trials that evaluate the safety and efficacy of acetaminophen in extremely preterm infants are needed.

Comparative Effect of the Active Substance of Thyme with N-Acetyl Cysteine on Hematological Parameters and Histopathological Changes of Bone Marrow and Liver in Rat Models of Acetaminophen Toxicity.

Acetaminophen has always been at the center of attention as a non-steroidal anti-inflammatory drug, which is generally associated with the serious side effects on liver and the hematological parameters. This study aimed to compare the effect of N-acetyl cysteine (NAC) and thyme extract on rat models of acetaminophen-induced toxicity. The present experimental study was conducted on 48 Wistar rats randomized into six groups, including the control group (no treatment); the Ac group (470 mg/kg of acetaminophen); the Ac + 100Ex, Ac + 200Ex, and Ac + 400Ex groups (acetaminophen + thyme extract at doses of 100, 200, 400 mg/kg); and Ac + NA group (acetaminophen + NAC). After weighing, a blood sample was taken from heart at the end of the period. The measured parameters were hematological, liver biochemical, and oxidative stress profiles. A part of the liver tissue was also fixed for the pathological examinations. The bone marrow was aspirated to check for cellular changes as well. The lowest mean of the final weight and liver weight to body weight ratio was observed in the Ac group. Weight loss was compensated in Ac + NA and Ac + 200Ex groups (P = 0.035). White blood cell (WBC), red blood cell (RBC), Hemoglobin (Hgb), and Hematocrit (HCT) in Ac and Ac + 400Ex groups showed significant differences from those of the other test groups (P < 0.001). Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) enzymes in Ac + 200Ex and Ac + NA groups showed a significant decrease compared to those of the other treatment groups (P = 0.043). Total antioxidant capacity (TAC) and glutathione peroxidase (GPx) had the lowest levels in Ac and Ac + 400Ex groups, while malondialdehyde (MDA) had the highest content. In this regard, the liver histopathological indices (necrosis, hyperemia, and hemorrhage) in the Ac + 200Ex and Ac + NA groups reached their lowest grades in the treatment groups. The mean number of erythroid and myeloid cells in the Ac group reached the lowest (17.40 ± 3.48). The microscopic appearance of the bone marrow cells was different from normocytosis in the control group to hypocytosis in the Ac and Ac + 400Ex groups. Thymol, as an effective ingredient in thyme extract at a dose of 200 mg/kg compared to NAC, had a unique effect on reducing bone marrow and liver cell-tissue changes due to the acetaminophen toxicity.

Transgenic Zebrafish Expressing Rat Cytochrome P450 2E1 (CYP2E1): Augmentation of Acetaminophen-Induced Toxicity in the Liver and Retina.

Metabolic activation is the primary cause of chemical toxicity including hepatotoxicity. Cytochrome P450 2E (CYP2E) is involved in this process for many hepatotoxicants, including acetaminophen (APAP), one of the most common analgesics and antipyretics. Although the zebrafish is now used as a model for toxicology and toxicity tests, the CYP2E homologue in zebrafish has not been identified yet. In this study, we prepared transgenic zebrafish embryos/larvae expressing rat CYP2E1 and enhanced green fluorescent protein (EGFP) using a β-actin promoter. Rat CYP2E1 activity was confirmed by the fluorescence of 7-hydroxycoumarin (7-HC), a metabolite of 7-methoxycoumarin that was specific for CYP2 in transgenic larvae with EGFP fluorescence (EGFP [+]) but not in transgenic larvae without EGFP fluorescence (EGFP [-]). APAP (2.5 mM) caused reduction in the size of the retina in EGFP [+] larvae but not in EGFP [-] larvae, while APAP similarly reduced pigmentation in both larvae. APAP at even 1 mM reduced the liver size in EGFP [+] larvae but not in EGFP [-] larvae. APAP-induced reduction of liver size was inhibited by N-acetylcysteine. These results suggest that rat CYP2E1 is involved in some APAP-induced toxicological endpoints in the retina and liver but not in melanogenesis of the developing zebrafish.

Ameliorative potential of ethanol leaf extract of Ficus exasperata in acetaminophen-induced toxicity in albino rats

Ameliorative potential of ethanol leaf extract of Ficus exasperata in acetaminophen-induced toxicity in albino rats

Jasminum elongatum Ameliorates Acetaminophen Induced Hepatotoxicity by Modulating Dysregulated Antioxidant Enzyme System

Objectives To evaluate the hepatoprotective activity of fractions of Jasminum elongatum methanolic extract against acetaminophen-induced hepatic damage. Materials and Methods Fractions obtained from methanolic extract of J. elongatum (petroleum ether, chloroform and hydroalcoholic) were investigated for hepatoprotective activity. Doses of 100 mg/kg and 200 mg/kg of different fractions were administered for 7 days, and acetaminophen toxicity was induced on the eighth day. After 24 hr of toxicity induction, biochemical markers and histological alterations were measured to determine the amount of hepatoprotection. Results The chloroform and hydroalcoholic fractions showed a significant decrease in biochemical parameters when compared to the toxic group, which was confirmed by histopathological changes and antioxidant parameters. Conclusion The results of this study revealed that the chloroform and hydroalcoholic fraction of J. elongatum have significant hepatoprotective activity against acetaminophen-induced toxicity.

Generation & characterization of expandable human liver sinusoidal endothelial cells and their application to assess hepatotoxicity in an advanced in vitro liver model

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells forming the hepatic sinusoidal wall. Besides their high endocytic potential, LSECs have been demonstrated to markedly contribute to liver homeostasis and immunity, and may partially explain unexpected hepatotoxicity of drug candidates. However, their use for in vitro investigations is compromised by poor cell yields and a limited proliferation capacity. Here, we report the transient expansion of primary human LSECs from three donors by lentiviral transduction. Transduced (“upcyte®”) LSECs were able to undergo at least 25 additional population doublings (PDs) before growth arrest due to senescence. Expanded upcyte® LSECs maintained several characteristics of primary LSECs, including expression of surface markers such as MMR and LYVE-1 as well as rapid uptake of acetylated LDL and ovalbumin. We further investigated the suitability of expanded upcyte® LSECs and proliferating upcyte® hepatocytes for detecting acetaminophen toxicity at millimolar concentrations (0, 0.5, 1, 2, 5, 10 mM) in static 2D cultures and a microphysiological 3D model. upcyte® LSECs exhibited a higher sensitivity to acetaminophen-induced toxicity compared to upcyte® hepatocytes in 2D culture, however, culturing upcyte® LSECs together with upcyte® hepatocytes in a co-culture reduced APAP-induced toxicity compared to 2D monocultures. A perfused Dynamic42 3D model was more sensitive to acetaminophen than the 2D co-culture model. Cytotoxicity in the 3D model was evident by decreased cellular viability, elevated LDH release, reduced nuclei counts and impaired cell morphology. Taken together, our data demonstrate that transient expansion of LSECs represents a suitable method for generation of large quantities of cells while maintaining many characteristics of primary cells and responsiveness to acetaminophen.

Phytochemical Composition and Hepatoprotective Potential of Ethanolic Root Extract of Jatropha curcas in Acetaminophen-Induced Toxicity in Albino Wistar Rats

This study evaluated the phytochemical composition and hepatoprotective potential of ethanolic root extract of Jatropha curcas in acetaminophen-induced toxicity in wistar albino rats. The phytochemical screening and composition were determined using gas chromatography. Thirty albino rats weighing between 170 and 200 g were used, were separated into 5 groups. Group one was administered distilled water, 2 was administered 1000 mg/kg AC only, 3, 4 and 5 were administered 1000 mg/kg acetaminophen + 200 mg/kg extract, 1000 mg/kg acetaminophen + 400 mg/kg extract, 1000 mg/kg AC + 100 mg/kg Silymarin. Phytochemical composition of root of the plant showed saponin (55.7079 µg/g) lunamarine (34.3976 µg/g), kaempferol (32.7107 µg/g), rutin (20.7399 µg/g), sapogenin (11.2644 µg/g), phenol (4.1557 µg/g), anthocyanin (1.1946 µg/g), epicatechin (0.8303 µg/g) and catechin (0.1883 µg/g). The plasma ALP, AST, ALT and GGT activities of the negative control were 151.50±14.11 U/L, 48.00±7.19 U/L, 79.50 ± 2.14 U/L and 3.50± 0.45 U/L respectively. The plasma ALP, AST, ALT and GGT activities of group 3 were 78.50± 4.75 U/L, 23.00± 2.35 U/L, 49.00± 3.65 and 2.95 ± 0.17 U/L respectively, were significantly decreased when compared with the controls. The plasma total protein, albumin and total bilirubin levels of the negative control were 57.00± 0.86 g/l, 32.00 ± 0.86 g/l, 20.35 ± 0.83 µmol. The plasma total protein, albumin and total bilirubin levels of group 3 were 61.50± 2.14 g/l, 33.00± 0.86 g/l 11.15 ± 0.98 µmol respectively and were significantly increased when compared the controls. The significant improvement observed on the liver markers is suggestive of the hepatoprotective properties of Jatropha curcas.

Short-term Co-exposure of celery leaf powder exerts detoxifying action against acetaminophen-induced toxicity in fish gills

Acetaminophen (APAP) is one of the widely used health care products. After consumption, excess APAP is excreted along with its toxic metabolites as human waste into sewage and other aquatic systems. These serve as aquatic pollutants and affect aquatic organisms. Plants can remove, reduce and transform the acetaminophen from the contaminated water. Thus, the present study is aimed at exploring whether APAP + celery leaf powder (CE) exposure would protect the fish gills from the toxicity of APAP. The freshwater fish (Pangasius sutchi) were divided as Group 1 control (untreated), Group 2 APAP treated (500 mg/kg/24 h), Group 3 APAP + CE (500 mg/kg/24 h) co-exposed and Group 4 CE treated control. The gills of APAP-exposed fishes displayed the elevated levels of aquatic pollutions markers [aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)], increased oxidative stress markers, the altered enzymic and non-enzymic antioxidants activities, and abnormal histology. Whereas, these changes were minimized in the gills of APAP+CE exposed fish. The findings of the study suggest that the antioxidant effect of CE and a possible interacting ability of CE phytochemicals with APAP could protect the osmoregulatory organs of fish from the APAP polluted water.

Hepatoprotective Potential of Malabar Tamarind (Garcinia gummi-gutta) Fruit-Rind Extract in Acetaminophen-Induced Toxicity Through Modulation of CYP2E1 Gene Expression in Hepatic Cells of Wistar Rats

The present study was aimed to assess the hepatoprotective effect of ethanolic extract of Garcinia gummi-gutta (GGE) fruit rind on acetaminophen-induced toxicity in a rat model and to explore the possible mechanism of action by assessing hepatic histopathology, serum bio­chemical parameters and expression of CYP2E1 gene in hepatic cells. The group I and 11 animals served as normal control and hepatotoxic control group, respectively; while group III, IV and V were administrated with GGE fruit-rind extract @ 50, 100 & 200 mg kg-1 orally, respectively, for 10 days. The group VI (positive control) received drug silymarin @ 100 mg kg-1 day-1 orally for 10 days. Hepatotoxicity was induced by single oral administration of acetaminophen (2 g kg-1) on 8th day. The results revealed that the extract produced dose-dependent hepatoprotective effect against acetaminophen-induced hepatic damage by improving the serum bio­chemical profile towards the normal range. Histopathology of liver showed that pretreatment with fruit-rind extract attenuated the toxicant-induced hepatocellular necrosis and enhanced the regeneration of hepatic cells. The hepatic expression level of CYP2E1 gene was found down-regulated in a dose dependent manner in extract-treated group as compared to the normal control group. The study revealed remarkable hepatoprotective effect of GGE in acetaminophen-induced toxicity in rats through regeneration of hepatic cells and by decreasing the formation of reactive metabolite, NAPQ1 by modulation of CYP2E1 gene expression in liver.

The Performance of HepG2 and HepaRG Systems through the Glass of Acetaminophen-Induced Toxicity.

Investigation of drug-induced liver injuries requires appropriate in vivo and in vitro toxicological model systems. In our study, an attempt was made to compare the hepatocarcinoma HepG2 and the stem cell-derived HepaRG cell lines both in two- and three-dimensional culture conditions to find the most suitable model. Comparison of the liver-specific characteristics of these models was performed via the extent and mechanism of acetaminophen (APAP)-induced hepatotoxicity. Investigating the detailed mechanism of APAP-induced hepatotoxicity, different specific cell death inhibitors were used: the pan-caspase inhibitor zVAD-fmk and dabrafenib significantly protected both cell lines from APAP-induced cell death. However, the known specific inhibitors of necroptosis (necrostatin-1 and MDIVI) were only effective in differentiated HepaRG, which suggest a differential execution of activated pathways in the two models. By applying 3D culture methods, CYP2E1 mRNA levels could be elevated, but we failed to achieve a significant increase in hepatocyte function; hence, the 3D cultivation especially in APAP toxicity studies is not necessarily worth the complicated maintenance. Based on our findings, the hepatocyte functions of HepaRG may stand between the properties of HepG2 cells and primary hepatocytes (PHHs). However, it should be noted that in contrast to PHHs having many limitations, HepaRG cells are relatively immortal, having a stable phenotype and CYP450 expression.

Hydroxysafflor yellows alleviate thrombosis and acetaminophen-induced toxicity in vivo by enhancing blood circulation and poison excretion

BackgroundHydroxysafflor yellow A (HSYA) from the flower of Carthamus tinctorius (Safflower) has been reported to have various pharmacological effects. However, little is known about the bioactivities of other chemical constituents in Safflower and the relationship between enhancement of blood circulation and hepatoprotection by HSYA. PurposeThe present research was to evaluate the antithrombotic and hepatoprotective activities of HSYA and C, examine their mechanisms of actions, including influence on the excretion velocity of acetaminophen, and the relationship between the antithrombotic, hepatoprotective, and other bioactivities. MethodsThe hepatoprotective activities were examined by acetaminophen (APAP)-induced zebrafish toxicity and carbon tetrachloride (CCl4)-induced mouse liver injury. The concentrations of APAP in zebrafish and APAP that was excreted to the culture media were quantified by UHPLC-MS. The anti-thrombosis effect of HSYA and C were examined by the phenylhydrazine (PHZ)-induced zebrafish thrombosis. ResultsHSYA and HSYC showed robust protection on APAP-induced toxicity and PHZ-induced thrombosis. The hepatoprotective effects of HSYA and C were more potent than that of the positive control, acetylcysteine (61.7% and 58.0%, respectively, vs. 56.9% at 100 µM) and their antithrombosis effects were more robust than aspirin (95.1% and 86.2% vs. 52.7% at 100 µM). HSYA and C enhanced blood circulation, rescued APAP-treated zebrafish from morphological abnormalities, and mitigated APAP-induced toxicity in liver development in liver-specific RFP-expressing transgenic zebrafish. HSYC attenuated CCl4-induced mouse liver injury and regulated the levels of HIF-1α, iNOS, TNF-α, α-SMA, and NFκB in liver tissues. HSYA was also protective in a dual thrombotic and liver toxicity zebrafish model. By UHPLC-MS, HSYA accelerated the excretion of APAP. ConclusionHSYA and C are the bioactive constituents of Safflower that are responsible for the herbal drug's traditional use in promoting blood circulation to remove blood stasis. Safflower and its chalcone constituents may protect from damage due to exogenous or disease-induced endogenous toxins by enhancing the excretion velocity of toxins.

Transcriptional Evaluation of Antioxidant and Anti-Inflammatory Potential of Buchholzia coriacea in Acetaminophen-Induced Sub-Chronic Renal and Hepatic Toxicity

The aim of this research was to evaluate the possible renal and Hepato-protective effects of ethanolic extract of Buchholzia coriacea seed compared to N-acetylcysteine, on gene expression in the liver and kidneys of Wistar rats subjected to sub-chronic dose of paracetamol. Forty wistar rats were divided into eight groups of five rats in each group. Group 1 received only normal diet as control (CTRL). Groups 2-6 received 14.28 mg/kg body weight of Paracetamol (PM). After 6 hours, 200 mg/kg body weight of extract (E1) was given to group 3, 400 mg/kg body weight extracts (E2) given to group 4, 70 and 150 mg/kg body weight of N-acetylcysteine was administered to group 5 and 6 respectively. Groups 7 and 8 received only 200 and 400 mg/kg body weight of extract (E1 and E2) respectively. This schedule was maintained for 90 days.

Histopathological effect of aqueous bitter leaf extract (Vernonia amygdalina) on acetaminophen-induced liver damage in albino rat (Rattus norvegicus)

Liver diseases are a worldwide problem. Medicinal plants are being increasingly utilized to treat a wide variety of diseases, liver disorder inclusive. The effect of aqueous leaf extracts of Vernonia amygdalina on acetaminophen-induced liver damage via the assessment of the histopathological examination was examined. Five groups of albino rats were used (n = 5). Animals in group 1 were fed normal laboratory pellet and water ad libitum (Control); those in group 2 received 3000mg/kg of acetaminophen alone. Groups 3, 4 and 5 received 3000mg/kg of acetaminophen and in addition 50mg/kg Vernonia amygdalina leaf extract. 100mg/kg Vernonia amygdalina leaf extract and 200mg/kg Silymarin, respectively for 14 days. Twenty-four hours after the last administration, the animals were sacrificed. The organs (liver) was excised and used for the histopathological examination. Histological examinations of the liver showed acetaminophen-induced hepatotoxicity. Histology of the liver revealed altered cellular architecture (poor architecture, moderate to severe congestion of the portal vein as well as severe peri portal infiltration of inflammatory cells, the liver parenchyma also showed area with destroyed liver plates with severe hemorrhage and necrosis. The morphology of the hepatocytes showed some degenerated liver cells, the liver parenchyma also showed focal area of moderate aggregate of inflammatory cells) following administration of acetaminophen (Group 2). Normal histological features were restored after treatment with aqueous leaf extract of Vernonia amygdalina. The study has demonstrated that aqueous leaf extract of Vernonia amygdalina ameliorate liver of rats against acetaminophen-induced toxicity and modulates the adverse effects of acetaminophen on the liver

Evaluation of the Acute Hepatoprotective Potential of Hydroethanolic Extract of Duranta erecta L. Parts.

Liver disease is a major health problem and its treatment is costly in most developing countries with attendant adverse effects. This study aimed at determining the acute hepatoprotective efficacy of Duranta erecta hydroethanolic extracts of leaves, ripe and unripe fruits against CCl4-, and acetaminophen-induced hepatotoxicity in animals. Materials and Methods. CCl4 (1 mL/kg body weight in olive oil) and acetaminophen (500 mg/kg b.wt) were used to induce hepatotoxicity in the animals. Animals were treated with extracts at 250 mg/kg b.wt and standard drug, silymarin (100 mg/kg), for 7 days. Hepatoprotective efficacy was assessed by assaying serum biochemical markers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (γGT), bilirubin (Bil), antioxidative biomarkers including reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione transferase (GST), superoxide dismutase (SOD), malondialdehyde (MDA), hydrogen peroxidase (H202), and nitric oxide (NO), as well as histological observations. Results. Exposure of the animals to CCl4 and acetaminophen resulted in liver injury as evidenced by elevated ALT, AST, ALP, γGT, Bil, MDA, H2O2, and NO levels with resultant derangement in liver microarchitecture. Pretreatment with hydroethanolic extracts, particularly ripe fruits of Duranta erecta, led to a reduction in these indicators and an increase in GSH, GPx, GST, and SOD levels. Biochemical data were supported by improvement in liver structure. Conclusion. The findings suggest that hydroethanolic Duranta erecta ripe fruits extract possesses hepatoprotective and antioxidative activities against CCl4- and acetaminophen-induced toxicity and could be developed as a potent agent for drug-induced liver diseases.