Induced Liver Toxicity Research Articles

Protective effects of resveratrol against fumonisin B1-induced liver toxicity in mice.

The aim of this study was to investigate the effects of resveratrol against fumonisin B1 (FB1)-induced liver toxicity, as, to the best of our knowledge, these effects have not been investigated yet, even though the toxic effects and mechanisms of FB1 and the antioxidative effects of resveratrol are well known. 40 BALB/c mice were divided into control, FB1, resveratrol, and FB1+resveratrol groups. Control received saline for 14 days. The FB1 group received 2.25 mg/kg FB1 every other day for 14 days. The resveratrol group received 10 mg/kg resveratrol for 14 days. The FB1+resveratrol group received 2.25 mg/kg FB1 every other day and 10 mg/kg resveratrol every day for 14 days. All administrations were peritoneal. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total sialic acid (TSA) levels were analysed in serum samples, while total antioxidant status (TAS) and total oxidant status (TOS) were measured in the liver. Additionally, the liver tissue was examined for histopathological changes. AST, ALT, and TSA were significantly higher in the FB1 group than control. Resveratrol countered FB1 effects for all parameters, including TOS and TAS. Liver histology showed FB1-induced hyperaemia, infiltrations, and megalokaryosis in some hepatocytes. No pathological findings were detected in the control, resveratrol, or FB1+resveratrol group. Our findings confirm resveratrol's protective effect against liver damage and oxidative stress caused by FB1. In addition, they suggest that increased serum TSA levels can be used as a biomarker of FB1-induced hepatotoxicity.

Hepatoprotective effect of the Hexane extract of Luffa echinata root and Stem bark against Tetrachloromethane Induced Hepatic Disorder in rats

In many nations, long term liver syndromes are the principal cause of casualty. Medicinal drug obtained from fauna and floras are well-thought-out and valuable in the treatment of chronic diseases that require long-term treatment. An experiment was conducted to determine the potential outcome of a hexane extract of the root and stem bark of Luffa echinata (L.echinata) Roxb on tetra chloromethane (TCM) induced liver toxicity in female albino rats. The root and stem bark of L. echinata were treated with hexane (C6H6), and exposed to preliminary secondary metabolite screening for the presence of various therapeutic component. Tetra chloromethane has been used to cause the hepatic disease in albino rats, which was subsequently treated with Hexane extract. Biochemical markers including entire bilirubin (BR), serum glutamic–oxaloacetic transaminase (SGOT) enzyme, serum glutamic –pyruvic transaminase (SGPT) enzyme, and total serum protein (TSP) in blood serum were used to assess the patient. The synergistic outcome of root and stem bark hexane extract on the damage liver tissues were also investigated histopathologically. According to the findings, Hexane extract has a strong hepatoprotective effect.

Assessing Kidney Injury Induced by Mercuric Chloride in Guinea Pigs with In Vivo and In Vitro Experiments.

Acute kidney injury, which is associated with high levels of morbidity and mortality, affects a significant number of individuals, and can be triggered by multiple factors, such as medications, exposure to toxic chemicals or other substances, disease, and trauma. Because the kidney is a critical organ, understanding and identifying early cellular or gene-level changes can provide a foundation for designing medical interventions. In our earlier work, we identified gene modules anchored to histopathology phenotypes associated with toxicant-induced liver and kidney injuries. Here, using in vivo and in vitro experiments, we assessed and validated these kidney injury-associated modules by analyzing gene expression data from the kidneys of male Hartley guinea pigs exposed to mercuric chloride. Using plasma creatinine levels and cell-viability assays as measures of the extent of renal dysfunction under in vivo and in vitro conditions, we performed an initial range-finding study to identify the appropriate doses and exposure times associated with mild and severe kidney injuries. We then monitored changes in kidney gene expression at the selected doses and time points post-toxicant exposure to characterize the mechanisms of kidney injury. Our injury module-based analysis revealed a dose-dependent activation of several phenotypic cellular processes associated with dilatation, necrosis, and fibrogenesis that were common across the experimental platforms and indicative of processes that initiate kidney damage. Furthermore, a comparison of activated injury modules between guinea pigs and rats indicated a strong correlation between the modules, highlighting their potential for cross-species translational studies.

Tigecycline induced liver toxicity in a renal transplant recipient with hepatic histology imitating sepsis

Background: Tigecycline has an expanded broad-spectrum antibacterial activity including multi-drug resistant pathogens. A case of a renal transplant recipient with tigecycline- induced acute liver injury is presented.

Abstract 6338: Development of a novel MSLN × 4-1BB bispecific antibody

Abstract Background: 4-1BB (CD137) is not only expressed on the surface of activated T cells and NK cells, but also a marker for Treg cells. Mesothelin (MSLN) is a ~71 kDa cell surface glycoprotein that is rarely expressed in normal tissues but overexpressed in many types of tumors. The fastest progress of MSLN-targeted therapy is in clinical phase II currently, including antibodies, ADCs, immunotoxins, vaccines and CAR-T. Here, we developed a bispecific antibody (bsAb) targeting both MSLN and 4-1BB with an intact Fc fragment from human IgG1. It can simultaneously exert the cytotoxic effect of CD8+T cells and and NK cells on tumor cells expressing MSLN to achieve better antitumor efficacy. Methods: Firstly, two bsAbs with IgG-scFv format were constructed with IgG1 and IgG4, named as HK013-G1 and HK013-G4 respectively. Secondly, we evaluated the binding activities of two candidates to tumor cells with different MSLN expression levels and their effects on 4-1BB+ cell activation mediated by MSLN-crosslinking. Subsequently, the cell-killing abilities of NK and cytotoxic T cells induced by bsAbs were quantified. Finally, we compared the ability of bsAbs to inhibit tumor growth in vivo and their effects on intratumoral CD8+T cells and Tregs. The capacity of bsAb candidates to induce liver toxicity was investigated simultaneously in these immunocompetent mice. Moreover, to further confirm the safety of HK013-G1, the risk of cytokine release storm (CRS) and activation of 4-1BB signal mediated by Fc receptors (FcRs), which are responsible for the potential side effects of 4-1BB mAbs were also evaluated. Results: HK013-G1 is able to bind different MSLN-expressing cancer cells and bridge MSLN+ cells and 4-1BB+ cells. In luciferase reporter assay, the bsAb-induced 4-1BB activation is dependent on expression level of MSLN. While incubated with CD8+T cells, HK013-G1 increased IFN-γ production only in the presence of MSLN+ cells. Furthermore, HK013-G1 could exert its affects via both NK cell and activated PBMC. In MC38-hMSLN tumor models, HK013-G1 showed a more significant growth inhibition effect than HK013-G4, and did not show detectable liver damage. In addition, HK013-G1 could enhance the antitumor effect of anti-PD-1 in CT26-hMSLN tumor models. Also, HK013-G1 was shown no stronger ability to inducing CRS and activating 4-1BB signal in the presence of FcRs than HK013-G4 and parent anti-4-1BB mAb in vitro. Conclusions: HK013-G1, a MSLN × 4-1BB bsAb with human IgG1 Fc fragment prevents tumor development by killing tumor cells directly via effector functions mediated by NK and cytotoxic T cells. These results show that this bsAb has the potential to develop into a new clinical therapy for cancer types with high-level MSLN expression. Citation Format: Liangwei Li, Dayan Zhang, Guodong Shen, Wenting Liu, Xiaoli Zeng, Lingling Wu, Qun Zhao, Weiming Zhou, Yang Huang, Liansheng Cheng. Development of a novel MSLN × 4-1BB bispecific antibody. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6338.

The combined effect of Raspberry Ketone with Resveratrol against oxidative stress and steatohepatitis in rats: Pharmacokinetic and pharmacodynamic studies.

Raspberry Ketone (RK) and Resveratrol (RSV) are natural phenolic antioxidants and anti-inflammatory agents. However, its combined pharmacokinetic and pharmacodynamics potentials are not reported. The study aims to assess the combined effect of RK with RSV to protect rats from carbon-tetrachloride (CCl4) induced oxidative stress and NASH. The toxicant CCl4 was employed at a concentration of 1 mL/kg as a 1:1 (v/v) mixture with olive oil twice weekly for 6 weeks to induce liver toxicity. Animal treatment was followed for 2 weeks. Silymarin was used as a standard control drug to compare the hepatoprotective effect of RK and RSV. Hepatic histology, oxidative stress, MMP, reduced glutathione (GSH), plasma levels of SGOT, SGPT, and lipid profile (total cholesterol and triglycerides) were measured. Anti-inflammation genes (IL-10), and fibrotic genes (TGF-β) were also examined in liver tissue. Oral administration of combined RK with RSV (50 + 50 mg/kg for 2 weeks) showed significantly more hepatoprotection by significantly decreasing elevated plasma markers and lipid profile than alone RK and RSV (100 mg/kg daily for 2 weeks). It also significantly alleviated the hepatic lipid peroxidation, restoring the activities of GSH levels in the liver. RT-PCR and Immunoblotting studies confirmed that significantly upregulation of anti-inflammation genes and protein expression (MMP-9) ameliorated the disease. Pharmacokinetic studies confirmed more synergistic stability in simulated gastric-intestinal fluids (FaSSGF, FaSSIF) and rat liver microsomes (CYP-450, NADPH oxidation & glucuronidation. Moreover, coadministration of drugs augmented the relative bioavailability, Vd/ F (L/Kg), and MRT0-∞( h), which leads to more efficacy. This pharmacokinetic and pharmacodynamic reveals a new adjuvant therapy for the treatment of steatohepatitis.

Evaluating the Impact of Vitamin E Treatment on Paraquat Induced Toxicity in Liver

Paraquat is a weed destroyer utilized by agriculturists to safeguard their harvests against weed and increase crop yields. Paraquat has high gastrointestinal absorption rate and being very poisonous, it harms the liver, kidney, and the lungs by delivering free radicals, NF-KB activation, and apoptosis in numerous cells. The experimental study used. The average weight of 200 male Wistar rats was 200±20g. The two hundred rats were divided into four groups of fifty. The groups were labelled as A, B, C, and D. A control group received no paraquat, while groups B, C, and D received either 0.02g, 0.04g, or 0.06g of paraquat per kilogramme of rat every two weeks for three months. Each group consisted of two smaller groups. There were subgroups "A0" and "AVE" within the "A" group, "B0" and "BVE" within the "B" group, "C0" and "CVE" within the "C" group, and "D0" and "DVE" within the "D" group. Subgroups "A0," "B0," "C0," and "D0" did not receive vitamin E, while those in "AVE," "BVE," "CVE," and "DVE" did. subgroups weekly for one month after paraquat chronic treatment. Blood was acquired and assayed for liver function test. Aside from A0 grounp which is the control group, B0, C0, and D0 being the test groups (paraquat treated groups) as well as the BVE, CVE, and DVE vit. E treatment subgroups had a measurably significant difference, p-value≤0.05, in SGOT, SGPT, ALP, and GGT, a result which affirmed the toxic potential of paraquat and the ameliorative impact of vit. E. The outcomes showed that vitamin E treatment is strong against paraquat instigated liver toxicity on a one month weekly treatment plan.

Study of Role Flavonoid Compound Isolated from Camellia Sinensis (Black Tea) Extract against Methotrexate Drug Induced Liver Toxicity in Male Rate

Study of Role Flavonoid Compound Isolated from Camellia Sinensis (Black Tea) Extract against Methotrexate Drug Induced Liver Toxicity in Male Rate

Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity

BackgroundAgonistic anti-CD40 monoclonal antibodies (mAbs) have emerged as promising immunotherapeutic compounds with impressive antitumor effects in mouse models. However, preclinical and clinical studies faced dose-limiting toxicities mediated by necroinflammatory liver...

Insights into the toxicities of UV-328, UV-329, UV-P in HepG2 cells and their roles in AHR-mediated pathway

The widespread high concentrations of benzotriazole ultraviolet stabilizers (BUVSs) in many biotic and abiotic samples have raised urgent concerns of their adverse effects on environmental and human health. In this study, we investigated the toxicity of three typical BUVSs (UV-328, UV-329, UV-P) with HepG2 cells in vitro. Results indicated that the three BUVSs showed weak cytotoxicity in HepG2 cells at concentrations lower than 50 μM. Transcriptional analysis indicated that the toxic effects of the three chemicals followed the order of UV-P > UV-329 > UV-328. UV-P and UV-329 may act as potential environmental diabetogens by significantly enriching several diabetic related items in both GO and KEGG analysis. Moreover, UV-P and UV-329 significantly upregulated the expression of AHR target genes (CYP1A1, CYP1A2, UGT1A1, etc.), and increased the ethoxyresorufin-O-deethylase (EROD) activity and exhibited agonistic activity toward AHR in the XRE-mediated luciferase reporter gene assay. Molecular docking assay also indicated that UV-329 and UV-P had higher binding affinities to AHR-LBD than UV-328. In brief, our findings indicated that UV-P and UV-329 were potential agonist of AHR ligand, and may exert more toxicity than UV-328 in inducing liver toxicity.

Melissa Officinalis L. aqueous extract pretreatment decreases methotrexate-induced hepatotoxicity at lower dose and increases 99mTc-phytate liver uptake, as a probe of liver toxicity assessment, in rats.

Hepatotoxicity remains amongst the restricting factors of Methotrexate (MTX)-associated cancer therapy, especially in high doses of chemo-drugs or prolonged treatment. Due to the known protective effects ofMelissa officinalis(M. officinalis), the aqueous extract of this plant was evaluated to ameliorate MTX-associated hepatotoxicity in rats. Adult female Wistar rats were received or notM. officinalisaqueous extract at doses of 100mg/kg (for 14 and 24 consecutive days) and 2g/kg (for 14 consecutive days) by gavage technique. MTX (20mg/kg) was intraperitoneally injected on the 10th- and 20th-day post-M.officinalistreatment. 24h after the last day of treatment, 99mTc-phytate was intravenously injected through the tail of rats. Animals were killed at 20min after radiocolloid injection, and vital tissues including the liver and spleen were isolated, weighed, and their radioactivity was counted. As well, 99mTc-phytate scintigraphy and histopathology of the liver were performed for higher accuracy. A significant increase in liver radioactivity was detected inM. officinalis+MTX receiving groups compared with the MTX rats which were more robust at a dose of 100mg/kg for 14days. Also, a significant reduction in liver radioactivity was evident withM. officinalisextract at a dose of 2g/kg for 14days in comparison with the control group, this reduction was not significant at the lower dose of 100mg/kg. Gamma scintigraphy and histopathological examinations confirmed the hepatoprotective effect ofM. officinalisvs MTX-induced liver injury in rats. In conclusion, we highlighted the liver uptake of 99mTc-phytate as a valuable method for assessment of liver toxicity and addressed that M. officinalis pretreatment (100mg/kg for 14days) ameliorates the MTX-associated hepatotoxicity in rats; however, M. officinalis itself induces liver toxicity at higher doses.

Cannabinoids inhibit ethanol-induced activation of liver toxicity in rats through JNK/ERK/MAPK signaling pathways.

Cannabinoids (CBs) are psychoactive compounds, with reported anticancer, anti-inflammatory, and anti-neoplastic properties. The study was aimed at assessing the hepatoprotective effects of CB against ethanol (EtOH)-induced liver toxicity in rats. The animals were divided into seven groups: control (Group I) and Group II were treated with 50% ethanol (EtOH 5 mg/kg). Groups III, IV, and VI were treated with (EtOH + CB 10 mg/kg), (EtOH + CB 20 mg/kg), and (EtOH + CB 30 mg/kg), respectively. Groups V and VII consisted of animals treated with 20 and 30 mg/kg, of CB, respectively. Biochemical analysis revealed that Group IV (EtOH + CB 20 mg/kg) had reduced levels of ALT-alanine transferase, AST-aspartate aminotransferase, ALP-alanine peroxidase, MDA-malondialdehyde and increased levels of GSH-reduced glutathione. Histopathological analysis of liver and kidney tissues showed that EtOH + CB (20 and 30 mg/kg) treated animal groups exhibited normal tissue architecture similar to that of the control group. ELISA revealed that the inflammatory markers were reduced in the animal groups that were treated with EtOH + CB 20 mg/kg, in comparison to the animals treated only with EtOH. The mRNA expression levels of COX-2, CD-14, and MIP-2 showed a remarkable decrease in EtOH + CB treated animal groups to control groups. Western blot analysis revealed that CB downregulated p38/JNK/ERK thereby exhibiting its hepatoprotective property by inhibiting mitogen-activated protein kinasepathways. Thus, our findings suggest that CB is a potential candidate for the treatment of alcohol-induced hepatotoxicity.

Hepatoprotective effect of a polyherbal formulation (Aab-e-Murawaqain) against CCl4 induced liver toxicity in Wistar albino rat model by suppressing proinflammatory cytokines

This study assessed the hepatoprotective action of Aab-e-Murawaqain in Wistar albino rats by inducing liver injury with carbon tetra chloride (CCl 4 ) (2 mL/kg; sc). Aqueous extracts of Solanum nigrum (Makoy) and Cichorium intybus (Kashni) were used to prepare the Aab-e-Murawaqain polyherbal formulation. Silymarin (25 mg/kg), a well-known liver protective medicine, was treated as the reference control group. Biochemical indicators, such as serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), and total bilirubin, were used to assess the curative potential. Other common biomarkers, such as thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT), were also estimated. Animals treated with CCl 4 exhibited significantly enhanced in SGOT, SGPT, ALP, bilirubin, and TBARS level, reflecting hepatic damage. The formulation considerably minimised the increase serum enzyme levels, indicating the improvement in liver cellular injury. CCl 4 induced significant decrease in GSH, SOD, and CAT levels. Pretreatment of the rats with the formulation led to an increase in hepatic GSH, SOD, CAT, protein, and albumin levels. Moreover, CCl 4 administration led to an increase in TNF-α, IL-6, and IL-10 levels, which decreased with polyherbal formulation treatment. The results were validated through histological evolutions, which revealed minimum fatty variations and a noticeable regenerative effect in the livers after treatment with the formulation. The results confirmed that Aab-e-Murawaqain can provide a substantial activity in the management of CCl 4 -induced hepatotoxicity.

Baseline Liver Elastography Does Not Predict Risks of Hepato-Toxicity to Reduced Dose Inotuzumab Therapy Combined with Minihcvd in B-Cell Acute Lymphoblastic Leukemia

Background: Inotuzumab ozogamicin (InO) is an anti-CD22 antibody drug conjugate that is FDA approved for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-cell ALL). Liver toxicity, particularly veno-occlusive disease (VOD) was the most important grade 3 toxicity in the Phase III INO-VATE study of InO, driven by the active cytotoxic agent calicheamicin conjugated to InO, especially in pts who underwent subsequent stem cell transplantation (SCT) (Kantarjian et. al, NEJM 2016). However proper assessment of liver function and fibrosis through elastographic measurements might predict the risks of subsequent liver toxicity with InO. Aim: We aimed to study the extent of liver toxicity, including VOD, in pts treated with InO and its correlation to baseline liver elastography. Methods: Pts with B-cell ALL treated with InO containing low intensity combination regimen [miniCVD-InO- blinatumomab-rituximab (previously published; Jabbour et. al. Cancer 2018)] as part of a clinical trial (NCT01371630) underwent baseline liver elastography and were prospectively monitored for any evidence of liver toxicity, including VOD. Elastography was done within 4 weeks prior to the first infusion of InO and liver stiffness was stratified based on the median shear wave velocity (SWV) using the acoustic radiation force impulse (ARFI) technique. Elastographic median SWV >1.7 m/s was considered as evidence of definite liver fibrosis. We captured the patient characteristics, history of known liver disorders, baseline liver function tests, total dose of InO administered and any subsequent liver toxicities including VOD. Any antecedent or subsequent history of SCT was noted; liver toxicity was graded according to the NCI CTCAE, v5. The dose of InO was capped at a cumulative maximum of 2.7mg/m2 of body surface area (administered in fractionated doses) and all pts received concurrent ursodiol prophylaxis with InO. Results: From Jan 2018- April 2022, 50 consecutive pts treated with the above regimen and with baseline elastography reports available as part of the research protocol were analyzed. The median age of the pts was 54.9 years (yrs) (range, 21.7-87.7 yrs) and only 1 pt had a known prior liver ailment of non-alcoholic fatty liver disease (NAFLD). Baseline characteristics are mentioned in Table 1. The median InO dose received by the pts were 1.5 mg/m2 (range, 0.9-2.7 mg/m2) and only 11 pts (22%) received the maximum cumulative InO dose of 2.7 mg/m2. A total of 11 pts (22%) had a baseline maximum SWV >1.7 m/s which radiologically corresponds to possible compensated advanced chronic liver disease (cACLD) and no pts had a SWV >2.1 m/s (corresponds to clinically significant portal hypertension; CSPH). All pts achieved CR/CRi as best response and 14 pts (28%) underwent consolidative SCT. Only one pt developed a VOD of the liver, diagnosed based on clinical and radiological findings, at D+60 post haploidentical-SCT with Flu/Mel140 conditioning and post-transplant cyclophosphamide. This pt had normal baseline liver elastography and had received a cumulative InO dose of 1.5 mg/m2. Another 5-pts (10%) had ≥ grade 3 liver toxicity (1 pt with hyperbilirubinemia and 4 pts with ALT elevation), all of whom had baseline SWV <1.7 m/s on elastography. On regression analysis using age, cumulative InO dose, baseline values of total bilirubin, ALT and INR, and SWV cutoffs as covariates, no factor significantly affected the risks of ≥ grade 3 liver toxicity. After adopting the use of reduced dose fractionated InO administration regimen, routine ursodiol prophylaxis and avoiding peri-transplant azole antifungal prophylaxis in InO exposed B-cell ALL pts at our center, the frequency of liver toxicites including VOD has significantly reduced compared to the 11% rate of VOD described in the INO-VATE study. With these improvisations reducing the overall frequency of InO induced liver toxicity, the positive predictive value of a pre-InO elastography to envisage the risks of subsequent VOD and other liver toxicity in these pts is highly limited. Conclusion: In a prospectively monitored group of pts of B-cell ALL treated with fractionated InO containing combination regimen, baseline liver elastography did not predict the risk of subsequent liver toxicity. Sequential liver elastographies to monitor dynamic changes in SWV needs to be analyzed in future studies to further assess its predictive role for InO induced liver toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hepato-Protective Effect of Telfaria occidentalis (Ugwu) Leaves Supplementation in Paracetamol Induced-Toxicity in Rats

The hepato-protective effect of Telfaria occidentalis leaves supplementation on paracetamol induced liver toxicity in wistar rats was investigated. A total of forty Wistar (female and male) rats weighing between 150-250g were selected for the study. The animals were randomly divided into four groups of five animals each. Animals in group 1 and 2 received standard chow only while animals in group 3 and 4 received 5% and 10% T. occidentalis supplementation in their feed respectively for six weeks. Group 2, 3 and 4 were administered 3000 mg/kg bodyweight of paracetamol intraperitoneally after six weeks. The animals were sacrificed after 24hours of induction and the liver was harvested for analysis. Alanine transaminase, Aspartate Transaminase and Alkaline Phosphatase, total protein, total bilirubin and direct bilirubin were measured in the liver homogenate following standard methods. A significant decrease in the level of ALT, AST and ALP, Bilirubin and increased total protein in group 3 and 4 were observed when compared with group 2. This study showed that T. occidentalis leaves possess protective potential on the liver when supplemented in the diet thereby preventing deleterious effects that might arose from paracetamol overdose or overuse. The study concluded that the protective effect of the leaves on the liver is percentage supplementation (dose) dependent.

Hepatoprotective effects of walnut oil and Caralluma tuberculata against paracetamol in experimentally induced liver toxicity in mice.

Walnut Oil and Caralluma are edible and form part of the traditional medicine system in many countries. These are frequently used in traditional medicine as remedies to relieve a wide range of illnesses and health problems. Walnut Oil and Caralluma species have demonstrated anti-inflammatory, anti-nociceptive, antidiabetics, hepatoprotective, gastric mucosa protecting, antimalarial, antioxidant, anti-trypanosomal, appetite suppressant and cytotoxic activities. The current study was planned to study the impacts of 21 days' oral administration of walnut oil and methanolic extract of Caralluma tuberculata on the levels of some liver-associated parameters and hematological parameters in paracetamol intoxicated mice. It was observed that paracetamol intoxication resulted in a considerable rise in serum ALT, cholesterol, triglycerides, Creatinine, and urea levels while a decrease in HDL level in comparison to mice normal control group (P<0.05). Serum ALT, cholesterol, triglycerides, creatinine, and urea levels of mice that were administered with walnut oil and methanolic extract of C. tuberculata at the doses of (1 ml/kg, 2 ml/kg and 3 ml/kg body weight) were significantly lower when compared to toxic control mice group (P<0.05), While HDL level was significantly increased. The significant reduction had also been observed in the levels of serum parameters of mice group, which received standard hepato-protective drug i.e., vitamin C, at the dose of 8 mg/kg body weight (P<0.05). Based on these results, it was evident that liver toxicity caused by the paracetamol administration has recovered toward the normal range by the walnut oil and C. tuberculata extract. Therefore, the present study revealed that (walnut oil and C. tuberculata) exhibit hepatoprotective activities in paracetamol intoxicated mice.

Hepatoprotective Role Of N-Hexane Fraction And Crude Methanolic Extract Of Withania Coagulans In Balb C Mice.

Withania coagulans is one of the most important medicinal herbs due to its wide range of biological activities. The aim of this study was to compare the hepatoprotective activity of crude methanolic extract versus n- hexane fraction of fruit of Withania coagulans in CCl4 induced liver toxicity. This study was done on 36 Balb c mice in Department of Anatomy of Khyber Medical College Peshawar. The mean serum of Group 1(control Group) was 33.41±1.82U/L, for Group 2 (CCl4 treated Group) was 89.01±7.51 U/L, for Group 3(low dose Group) was 49.91±3.48 U/L and for Group 4 (High dose Group) was 50.86±4.87 U/L. There was significant difference in the readings of Group1 and Group 2 which indicated CCL4 induced hepatotoxicity in two groups. There was significant difference in the values of Group 3 and Group 4 (p value .000), showing the hepatotoxicity in these Groups was further enhanced. The mean AST at the end of six weeks for Group1 was 26.80±3.21U/L, for Group 2 was 149.01±13.63U/L, for Group 3 (including both low doses) was 70.81±7.92U/L and for Group 4 (High doses group) was 51.01±11.05U/. Withania coagulans both fractions have hepatoprotective effect against CCL4 induced hepatic toxicity in high and low doses in Balb c mice.

Ameliorative impact of herbal formulation -Majoon-Dabeed-ul-ward and Sharbat-e-Deenar against CCl4 induced liver toxicity via regulation of antioxidant enzymes and oxidative stress.

Polyherbal Unani formulations have been used in the treatment of liver diseases for a long time. (Ibrahim M, Khaja MN, Aara A, Khan AA, Habeeb MA, Devi YP, Narasu ML, Habibullah CM. Hepatoprotective activity of Sapindus mukorossi and Rheum emodi extracts: in vitro and in vivo studies. World J Gastroenterol. 2008:14:2566-2571.) The aim of the present study was to investigate comparative hepatoprotective potential of Majoon-e-Dabeed-ul-ward (MD) and Sharbat-e-Deenar (SD) against CCl4 induced subchronic hepatic toxicity. In vivo study, albino rats were divided into 5 groups. Group I was control; Group II was experimental control treated with CCl4 (0.15mL/kg, i.p. for 21days); Groups III-IV treated with SD (2mL/kg, p.o.) and MD (1,000mg/kg, p.o.) for 5days following CCl4 intoxication as in group 2 respectively; and Group V was positive control treated with silymarin (50mg/kg, p.o.). In vitro hepatoprotective activity of SD and MD (25, 50, and 100μg/mL) was assessed by SRB assay and flow cytometry analysis. CCl4 exposure significantly elevated the release of hepatic enzymes i.e. AST, ALT, LDH, and SALP in serum and lipid peroxidation in liver tissue which all these parameters were reversed after SD and MD administration. Therapy for 5days also normalized the levels of antioxidant enzymes i.e. catalase, SOD, GPx, GR, tissue GSH, and aniline hydroxylase in CCl4 treated group. DNA damage and histological alterations caused by CCl4 were restored towards normal group. In vitro study showed protective effect of SD and MD against CCl4 treated HepG2 cell lines and rat hepatocytes. The results suggested that MD has a significant hepatoprotective potential and regulatory effect on oxidative stress than SD against CCl4 induced hepatotoxicity, and that this effect may be related to its antioxidant activity.

Dexamethasone as an anti-cancer or hepatotoxic

The linkage between inflammation and oxidative stress in liver damage has been proven and is undeniable; dexamethasone with some antioxidants can reduce the toxicity of liver tissue. Due to the importance of cancer treatment, glucocorticoids' synergistic effect in inhibiting cancer cell growth is also investigated. Dexamethasone alone and combined with etoposide were tested at concentrations of 1, 5, and 10 μM to evaluate the potency of dexamethasone in inhibiting the growth of A549 cells using oxidative stress factors and DNA damage. Also, intraperitoneal injection of dexamethasone in rats was used to induce liver toxicity. Coenzyme Q10 at different concentrations (1, 10, and 50 mg/kg) was used as an antioxidant to assess the oxidative stress factors and measure Caspase-3 activity. The results showed that dexamethasone combined with etoposide could significantly inhibit the growth of cancer cells and induce apoptosis. Treatment of A549 cells using dexamethasone also inhibits cancer cells' growth by inducing oxidative stress and DNA damage. Dexamethasone also, by inducing oxidative stress and activation of caspase 3, ultimately causes hepatotoxicity. Treatment with different concentrations of CoQ10 showed improved mitochondrial function, antioxidant defense, and liver enzyme. The best effect of coenzyme Q10 on dexamethasone-induced hepatotoxicity is 50 mg/kg. As a result, dexamethasone (alone and combined with etoposide) has an anti-cancer effect by damaging DNA and inducing oxidative stress. Also, CoQ10 has antioxidant effects against dexamethasone-induced hepatotoxicity by improving mitochondrial function and reducing caspase-3 activity.

Hepatocellular Recovery of Chronic Paraquat Induced Liver Toxicity in Vitamin E and C Treated Male Wistar Rats

Paraquat is an organic compound also known as methyl viologen, a chemical herbicide or weed killer with highly toxic effect on ingestion or exposure. Vitamin E and C are powerful antioxidants that act as initial responder against oxygen reactive species called free radicals which attack and destroy the tissues. The aim of this study was to determine a short term therapeutic effect of vitamin E and C combination on liver enzymes parameters of paraquat induced liver toxicity in male albino rats. 200 male albino rats were used for the study. The 200 rats were divided into four main groups (A, B, C, D) consisting of 50 rats in each group. The Groups were further divided into two subgroups having 25 rats in each subgroup. “A” group was not induced with paraquat while “B”, ‘C” and “D” groups were induced with increasing dose of 0.02g, 0.04g and 0.06g of paraquat respectively. “A” group had two subgroups; “Ao” and “AVEC” which represented the sub-group not treated with Vit E and the subgroup treated with Vit E (500mg) respectively. This also applied to group “B”, “C” and “D” paraquat was administered every forth night followed by treatment with the vitamins for one month. Blood samples were collected and analysed for liver function (SGOT, SGPT, ALT And GGT). There was a significant increase in the level of the liver enzymes among the “Ao”, “Bo”, “Co” and “Do”, p-value&lt;0.05 and also among the “AVEC”, “BVEC”, “CVEC” and “DVEC”, p-value&lt;0.05. The result also showed that there were significant differences in intra-group comparison in all the liver enzyme parameters, p-value&lt;0.05 while there was no significant difference among the AO and AVEC subgroups for all parameters. This study has shown that vitamin E and C combination has a therapeutic effect in male albino rats on one month of weekly treatment. Therefore, a weekly treatment with Vit E and C may treat liver disease toxicity associated with paraquat toxicity in rats.