Acute Hepatotoxicity Research Articles

Hepatoprotective Effect of Callicarpa lanata (L.) against Antituberculosis Treatment-induced Acute Hepatotoxicity

Hepatoprotective Effect of Callicarpa lanata (L.) against Antituberculosis Treatment-induced Acute Hepatotoxicity

Novel detoxifier of spironolactone against triptolide-induced hepatotoxicity through inhibition of RPB1 degradation

Ethnopharmacological relevanceTriptolide is a major bioactive and toxic ingredient isolated from the traditional Chinese herb Tripterygium wilfordii (T. wilfordii) Hook F. It exhibits potent antitumor, immunosuppressive, and anti-inflammatory biological activities; however, its clinical application is hindered by severe systemic toxicity. Two preparations of T. wilfordii, including T. wilfordii glycoside tablets and T. wilfordii tablets, containing triptolide, are commonly used in clinical practice. However, their adverse side effects, particularly hepatotoxicity, limit their safe use. Therefore, it is crucial to discover potent and specific detoxification medicines for triptolide. Aim of the studyThis study aimed to investigate the detoxification effects and potential mechanism of action of spironolactone on triptolide-induced hepatotoxicity to provide a potential detoxifying strategy for triptolide, thereby promoting the safe applications of T. wilfordii preparations in clinical settings. Materials and methodsCell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and crystal violet staining. Nuclear fragmentation was visualized using 4′,6-diamidino-2-phenylindole (DAPI) staining, and protein expression was analyzed by Western blotting. The inhibitory effect of spironolactone on triptolide-induced hepatotoxicity was evaluated by examining the effects of spironolactone on serum alanine aminotransferase and aspartate aminotransferase levels, as well as liver pathology in a mouse model of triptolide-induced acute hepatotoxicity. Furthermore, a survival assay was performed to investigate the effects of spironolactone on the survival rate of mice exposed to a lethal dose of triptolide. The effect of spironolactone on triptolide-induced global transcriptional repression was assessed through 5-ethynyl uridine staining. ResultsTriptolide treatment decreased the cell viability, increased the nuclear fragmentation and the cleaved caspase-3 levels in both hepatoma cells and hepatocytes. It also increased the alanine aminotransferase and aspartate aminotransferase levels, induced the hepatocyte swelling and necrosis, and led to seven deaths out of 11 mice. The above effects could be mitigated by pretreatment with spironolactone. Additionally, molecular mechanism exploration unveiled that spironolactone inhibited triptolide-induced DNA-directed RNA polymerase II subunit RPB1 degradation, consequently increased the fluorescence intensity of 5-ethynyl uridine staining for nascent RNA. ConclusionsThis study shows that spironolactone exhibits a potent detoxification role against triptolide hepatotoxicity, through inhibition of RPB1 degradation induced by triptolide and, in turn, retardation of global transcriptional inhibition in affected cells. These findings suggest a potential detoxification strategy for triptolide that may contribute to the safe use of T. wilfordii preparations.

Acute sleep deprivation-induced hepatotoxicity and dyslipidemia in middle-aged female rats and its amelioration by butanol extract of Tinospora cordifolia

BackgroundSleep deprivation (SD) due to an unhealthy lifestyle poses an oxidative challenge and is closely associated with an increased risk and prevalence of different metabolic disorders. Although the negative consequences of SD are well reported on mental health little is known about its detrimental effects on liver function and lipid metabolism. Tinospora cordifolia is reported for its hepatoprotective activity in different pre-clinical model systems. The current study was designed to elucidate the cumulative effects of aging and acute SD on liver functions, oxidative stress, and lipid metabolism, and their management by butanol extract of T. cordifolia (B-TCE) using middle-aged female acyclic rats as the model system.ResultsRats were divided into 4 groups: (1) Vehicle-undisturbed (VUD) (2) Vehicle-sleep deprived (VSD) (3) B-TCE pre-treated sleep-deprived (TSD) (4) B-TCE pre-treated undisturbed sleep (TUD). TSD and TUD groups were given 35 mg/kg of B-TCE once daily for 15 days followed by 12 h of sleep deprivation (6 a.m.–6 p.m.) of VSD and TSD group animals using the gentle-handling method while VUD and TUD group animals were left undisturbed. SD of VSD group animals increased oxidative stress, liver function disruption, and dyslipidemia which were ameliorated by B-TCE pre-treatment. Further, B-TCE was observed to target AMPK and its downstream lipid metabolism pathways as well as the p-Akt/cyclinD1/p-bad pathway of cell survival as possible underlying mechanisms of its hepatoprotective activity.ConclusionsThese findings suggest that B-TCE being a multi-component extract may be a potential agent in curtailing sleep-related problems and preventing SD-associated hepatotoxicity and dyslipidemia in postmenopausal women.Graphical abstractGraphical abstract to depict mechanism of action of B-TCE on liver function and lipid metabolism.

Cereblon deficiency ameliorates carbon tetrachloride-induced acute hepatotoxicity in HepG2 cells by suppressing MAPK-mediated apoptosis.

The liver is vulnerable to various hepatotoxins, including carbon tetrachloride (CCl4), which induces oxidative stress and apoptosis by producing reactive oxygen species (ROS) and activating the mitogen-activated protein kinase (MAPK) pathway. Cereblon (CRBN), a multifunctional protein implicated in various cellular processes, functions in the pathogenesis of various diseases; however, its function in liver injury remains unknown. We established a CRBN-knockout (KO) HepG2 cell line and examined its effect on CCl4-induced hepatocellular damage. CRBN-KO cells exhibited reduced sensitivity to CCl4-induced cytotoxicity, as evidenced by decreased levels of apoptosis markers, such as cleaved caspase-3, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. CRBN deficiency enhanced antioxidant defense, with increased superoxide dismutase activity and glutathione ratios (GSH/GSSG), as well as reduced pro-inflammatory cytokine expression. Mechanistically, the protective effects of CRBN deficiency appeared to involve the attenuation of the MAPK-mediated pathways, particularly through decreased phosphorylation of JNK and ERK. Overall, these results suggest the crucial role of CRBN in mediating the hepatocellular response to oxidative stress and inflammation triggered by CCl4 exposure, offering potential clinical implications for liver injury in a wide range of liver diseases.

Acute hepatotoxicity of intravenous amiodarone in a Becker muscular dystrophy patient with decompensated heart failing and ABCB4 gene mutation: as assessed for causality using the updated RUCAM

BackgroundCardiac dysfunction, including arrhythmias, may be one of the main clinical manifestations of Becker muscular dystrophy (BMD). Amiodarone is widely used to treat arrhythmia. However, multi-systemic toxicity caused by amiodarone, especially hepatotoxicity, should not be neglected. Here, we introduce a novel case of multi-systemic amiodarone toxicity involving the liver, renal and coagulation in BDM patient with ABCB4 gene mutation.Case presentationWe present a case of a 16-year-old boy admitted with heart failure and atrial fibrillation (AF). He was diagnosed with Becker muscular dystrophy (BMD) and gene testing showed comorbid mutations in gene DMD, ABCB4 and DSC2. Amiodarone was prescribed to control the paroxysmal atrial fibrillation intravenously. However, his liver enzyme levels were sharply elevated, along with cardiac shock, renal failure and coagulation disorders. After bedside continuous renal replacement therapy, the patient’s liver function and clinical status rehabilitated.ConclusionsABCB4 gene mutation might be involved in amiodarone-induced hepatotoxicity. Studies in a cohort might help to prove this hypothesis in the future.

Chlorogenic acid mitigates potassium dichromate-induced acute hepato-nephrotoxicity by attenuating the NF-κB signalling pathway.

Hexavalent chromium (CrVI) is known to be a potentially hepatotoxic and nephrotoxic contaminant in humans and other animals, whose toxicity is associated with oxidative stress and inflammation. The aim of this study was to evaluate the potential protective effect of chlorogenic acid (CGA), which has known anti-inflammatory and antioxidant effects, on potassium dichromate (PDC)-induced acute hepatotoxicity and nephrotoxicity in rats. Thirty-six Wistar albino rats were treated with CGA (10, 20, or 40mg/kg, intraperitoneally) and/or PDC (15mg/kg/day, intraperitoneally) as a single dose. Serum, liver, and kidney tissues were examined biochemically, histopathologically, and immunohistochemically. Compared to the control group, a significant increase in interleukin-6 (IL-6) levels and a significant decrease in serum and renal reduced glutathione (GSH) levels, liver catalase (CAT), tumour necrosis factor-alpha (TNF-α), and interleukin 1β (IL-1β) levels were observed in the PDC group. The administration of PDC led to histopathological and immunohistochemical changes in rat liver and kidney tissues. With the administration of CGA, especially at the 10mg/kg dosage, the above-mentioned parameters approached normal levels. CGA had antioxidant and anti-inflammatory effects that alleviated PDC-induced acute hepato- and nephrotoxicity.

Dissecting Acute Drug-Induced Hepatotoxicity and Therapeutic Responses of Steatotic Liver Disease Using Primary Mouse Liver and Blood Cells in a Liver-On-A-Chip Model.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is hallmarked by hepatic steatosis, cell injury, inflammation, and fibrosis. This study elaborates on a multicellular biochip-based liver sinusoid model to mimic MASLD pathomechanisms and investigate the therapeutic effects of drug candidates lanifibranor and resmetirom. Mouse liver primary hepatocytes, hepatic stellate cells, Kupffer cells, and endothelial cells are seeded in a dual-chamber biocompatible liver-on-a-chip (LoC). The LoC is then perfused with circulating immune cells (CICs). Acetaminophen (APAP) and free fatty acids (FFAs) treatment recapitulate acute drug-induced liver injury and MASLD, respectively. As a benchmark for the LoC, multiplex immunofluorescence on livers from APAP-injected and dietary MASLD-induced mice reveals characteristic changes on parenchymal and immune cell populations. APAP exposure induces cell death in the LoC, and increased inflammatory cytokine levels in the circulating perfusate. Under FFA stimulation, lipid accumulation, cellular damage, inflammatory secretome, and fibrogenesis are increased in the LoC, reflecting MASLD. Both injury conditions potentiate CIC migration from the perfusate to the LoC cellular layers. Lanifibranor prevents the onset of inflammation, while resmetirom decreases lipid accumulation in hepatocytes and increases the generation of FFA metabolites in the LoC. This study demonstrates the LoC potential for functional and molecular evaluation of liver disease drug candidates.

Prediction of Acute Hepatotoxicity With Human Pluripotent Stem Cell-Derived Hepatic Organoids.

Recent development of hepatic organoids (HOs) derived from human pluripotent stem cells (hPSCs) provides an alternative in vitro model that can mimic the human liver detoxification pathway for drug safety assessment. By recapitulating the high level of maturity and drug-metabolizing capacity of the liver in a three-dimensional organoid culture, HOs may allow researchers to assess drug toxicity and metabolism more accurately than animal models or hepatocellular carcinoma cells. Although this promising potential has contributed to the development of various protocols, only a few protocols are available to generate functional HOs with guaranteed CYP450 enzymatic activity, the key feature driving toxic responses during drug metabolism. Based on previously published protocols, we describe an optimized culture method that can substantially increase the expression and activity of CYP450s, in particular CYP3A4, CYP2C9, and CYP2C19, in HOs. To generate mass-produced and highly reproducible HOs required as models for toxicity evaluation, we first generated hepatic endodermal organoids (HEOs) from hPSCs capable of in vitro proliferation and cryopreservation. The stepwise protocol includes generating HEOs as well as efficient methods to enhance CYP450 expression and activity in terminally differentiated HOs. Furthermore, we present a simple protocol for the assessment of HO cytotoxicity, one of the hallmarks of drug-induced acute hepatotoxicity. The protocols are relatively straightforward and can be successfully used by laboratories with basic experience in culturing hPSCs. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Generation of hepatic endodermal organoids from human pluripotent stem cells Basic Protocol 2: Expansion and cryopreservation of hepatic endodermal organoids Basic Protocol 3: Differentiation of hepatic organoids from hepatic endodermal organoids Basic Protocol 4: Evaluation of hepatotoxicity using hepatic organoids Support Protocol: Human pluripotent stem cell culture.

Therapeutic benefit of oregano oil in the acute idiosyncratic hepatotoxicity induced by carbon tetrachloride in rats: Adverse effects of high dose of oreganum.

Toxicity caused by carbon tetrachloride (CCl4) can lead to serious liver injury. The aim of the study is to investigate the protective effects of oregano oil (Origanum minutiflorum extract oil) against CCl4-induced liver injury. Two doses of oregano oil were used in the experiment: a low dose (LD; 20 mg/kg) and a high dose (HD; 60 mg/kg) during 2 weeks. CCl4 caused severe liver damage, nucleolus destruction in hepatocytes and cytogenetic changes in the nucleus. Indirectly, CCl4 causes decreased protein synthesis and significantly high creatinine and urea values. Hematological disorders have been recorded, such as decreased RBC and hemoglobin concentration, increased WBC and deformability of the erythrocyte membrane. Both doses of oregano oil had protective effects. Improved protein synthesis and high globulins level, creatinine and urea were found in both groups. Cytogenetic changes in the nucleus of hepatocytes were reduced. A high dose of oregano oil had maximal protective effects for RBC, but a very weak effect on hemoglobin synthesis. Also, WBC and lymphocyte values were low. Origanum stimulates protein synthesis and recovery of hepatocytes after liver injury, reduces the deformability of the erythrocyte membrane. High doses of oregano oil decreased WBC and lymphocytes which may lead to a weakening of the immune response. However, high doses are more effective against severe platelet aggregation than low doses, suggesting an effective treatment against thrombocytosis.

Difference in the Mechanism of Iron Overload-Enhanced Acute Hepatotoxicity Induced by Thioacetamide and Carbon Tetrachloride in Rats.

Iron overload has been recognized as a risk factor for liver disease; however, little is known about its pathological role in the modification of liver injury. The purpose of this study is to investigate the influence of iron overload on liver injury induced by two hepatotoxicants with different pathogenesis in rats. Rats were fed a control (Cont), 0.8% high-iron (0.8% Fe), or 1% high-iron diet (1% Fe) for 4 weeks and were then administered with saline, thioacetamide (TAA), or carbon tetrachloride (CCl4). Hepatic and systemic iron overload were seen in the 0.8% and 1% Fe groups. Twenty-four hours after administration, hepatocellular necrosis induced by TAA and hepatocellular necrosis, degeneration, and vacuolation induced by CCl4, as well as serum transaminase values, were exacerbated in the 0.8% and 1% Fe groups compared to the Cont group. On the other hand, microvesicular vacuolation induced by CCl4 was decreased in 0.8% and 1% Fe groups. Hepatocellular DNA damage was increased by iron overload in both models, whereas a synergistic effect of oxidative stress by excess iron and hepatotoxicant was only present in the CCl4 model. The data showed that dietary iron overload exacerbates TAA- and CCl4-induced acute liver injury with different mechanisms.

The potential health risks of N,N-dimethylformamide: An updated review.

N,N-dimethylformamide (DMF) is a universally used industrial material with exponential growth in production and consumption worldwide. The frequently reported occupational DMF poisoning cases in some countries and the gradually recognized unavoidable health risks to the general population highlight that DMF should still be a matter of concern. Previous studies have demonstrated that the liver is the primary target organ of DMF exposure and multiple mechanisms have been revealed. However, most of these studies investigate the detrimental effects of acute and subacute DMF exposure, while the effects of chronic DMF exposure are rarely studied. Furthermore, the key mechanism for the acute hepatotoxicity of DMF remains to be elucidated. Future research may focus on the identification of efficient preventive measures against the toxicity of DMF to occupational workers, the investigation of the detrimental effects of DMF at environmentally relevant doses, and the studies on the elimination and recycling of DMF in industrial wastes. Herein, we present an updated review of the metabolism of DMF, the biomarker of DMF exposure, underlying molecular mechanisms of DMF-induced hepatotoxicity, and the toxicity of DMF to both occupational workers and general populations and discuss the possible directions in future studies.

The Protective Effect of Roflumilast Against Acute Hepatotoxicity Caused by Methotrexate in Wistar Rats: In vivo Evaluation.

Methotrexate (MTX) is one of the most widely used drugs in cancer chemotherapy and treating rheumatoid arthritis. The hepatotoxicity of MTX is one of its major side effects. Roflumilast (ROF) has been recognized to have antioxidant and anti-inflammatory activity in in-vivo and in-vitro models. The present study aimed to explore the potential protective effects of roflumilast against MTX-induced liver toxicity in male Wistar rats. High dose of 5 mg/kg for 4 consecutive days subcutaneous (S.C) injection of methotrexate for induction of acute liver injury. A total of 24 Wistar rats, rats were used in four different groups. The NS injections were given S.C to the control group once a day for 4 consecutive days. SC injections of MTX (5 mg/kg) were given to the MTX group daily for four days. At 5 mg/kg once daily for four days, the roflumilast group was given daily oral roflumilast. An injection of MTX and oral roflumilast were given to the MTX + roflumilast group once daily for four consecutive days. Administration of high dose MTX (5 mg/kg) today 4 produced a significant decrease in hepatic glutathione (GSH) levels and a significant increase in ALT and AST liver enzymes, hepatic malondialdehyde (MDA), tumor suppressor protein (p53), interleukin 6, interleukin 1 levels compared to the control group. Treatment with roflumilast for 4 days significantly attenuated unfavorable changes in these parameters. According to histopathological findings, Roflumilast significantly reduced MTX-induced inflammation and degeneration in the liver. In conclusion, the findings indicate that roflumilast may have a potential therapeutic benefit in treating rats with MTX-induced liver toxicity by mitigating its effects. The aim of this study is to investigate the potential protective effects of roflumilast against MTX-induced liver toxicity in Wistar rats.

Mitigation of Acute Hepatotoxicity Induced by Cadmium Through Morin: Modulation of Oxidative and Pro-apoptotic Endoplasmic Reticulum Stress and Inflammatory Responses in Rats

Cadmium (Cd) is a toxic heavy metal with significant environmental health hazards. It enters the body through various routes with tissue accumulation. The relatively longer half-life with slow body clearance significantly results in hepatotoxicity during its liver detoxification. Therefore, researchers are exploring the potential use of herbal-derived phytocomponents to mitigate their toxicity. Here, we investigated, for the first time, the possible ameliorative effect of the phytochemical Morin (3,5,7,29,49-pentahydroxyflavone) against acute Cd-induced hepatotoxicity while resolving its underlying cellular mechanisms in a rat animal model. The study involved 50 adult male Sprague–Dawley rats weighing 200–250 g. The animals were divided into five equal groups: control, Cd, Morin100 + Cd, Morin200 + Cd, and Morin200. The 2nd, 3rd, and 4th groups were intraperitoneally treated with Cd (6.5 mg/kg), while the 3rd, 4th, and 5th groups were orally treated with Morin (100 and 200 mg/kg) for 5 consecutive days. On the 6th day, hepatic function (serum ALT, AST, ALP, LDH enzyme activities, and total bilirubin level) testing, transcriptome analysis, and immunohistochemistry were performed to elucidate the ameliorative effect of Morin on hepatotoxicity. In addition to restoring liver function and tissue injury, Morin alleviated Cd-induced hepatic oxidative/endoplasmic reticulum stress in a dose-dependent manner, as revealed by upregulating the expression of antioxidants (SOD, GSH, Gpx, CAT, and Nrf2) and decreasing the expression of ER stress markers. The expression of the proinflammatory mediators (TNF-α, IL-1-β, and IL-6) was also downregulated while improving the anti-inflammatory (IL-10 and IL-4) expression levels. Morin further slowed the apoptotic cascades by deregulating the expression of pro-apoptotic Bax and Caspase 12 markers concomitant with an increase in anti-apoptotic Blc2 mRNA expression. Furthermore, Morin restored Cd-induced tissue damage and markedly suppressed the cytoplasmic expression of JNK and p-PERK immunostained proteins. This study demonstrated the dose-dependent antioxidant hepatoprotective effect of Morin against acute hepatic Cd intoxication. This effect is likely linked with the modulation of upstream p-GRP78/PERK/ATF6 pro-apoptotic oxidative/ER stress and the downstream JNK/BAX/caspase 12 apoptotic signaling pathways.

ПИЩЕВОЙ ПЕПТИД ДЛЯ ПРЕДУПРЕЖДЕНИЯ ИЗБЫТОЧНОЙ МАССЫ ТЕЛА: ВИРТУАЛЬНЫЙ СКРИНИНГ ПРОГНОЗИРОВАНИЯ ТОКСИЧНОСТИ И ВЫВЕДЕНИЯ

The aim of the research is to predict the toxicity and excretion of a biopeptide that prevents obesity. A synthesized peptide with the following sequence of amino acids was used as object of research: CHAECGAACKEFCLEG, preventing overweight. The peptide has similarities to glucagon-like peptide-1 (GLP-1), which regulates energy metabolism. Peptide characterization is the following: total hydrophobic ratio is 53 %, total charge is +0.25, hydrophobicity of the peptide according to Wimley-White in whole residue is 4.63, molecular weight 1556.826 Da, molecular formula C62H97N19O20S4, protein binding potential (Boman index) is 0.93 kcal / mol, isoelectric point pH 6.77. The peptide is highly soluble in water. The study established that the studied peptide, when ingested, does not cause acute toxicity, hepatotoxicity and cytotoxicity, does not adversely affect heart activity, does not activate heat shock protein gene receptors, does not cause DNA damage and mitochondrial dysfunction. The peptide is characterized by average half-life and low plasma clearance, which makes it effective. It should be noted that predicted characteristics do not always coincide with actual values obtained in in vitro experiments. Therefore, it is possible to recommend the peptide for inclusion in composition of specialized and preventive food products, provided that its effectiveness is proven in preclinical and clinical studies.

The hepatoprotective effects of sitagliptin against cyclophosphamide-induced hepatotoxicity in rat.

Hepatotoxicity is a serious side effects of cyclophosphamide. Thus, the present research investigates the protective properties of sitagliptin against cyclophosphamide-induced hepatotoxicity. Fifty male rats were randomly divided into five groups. They were pre-treated with either sitagliptin or normal saline once a day for the first ten days of the study. To induce acute hepatotoxicity, cyclophosphamide (200 mg/kg, i.p) was injected only one time and 45 min after the last dose of sitagliptin. The rats were sacrificed on the 11th day, and their blood and liver were collected for biochemical, gene expression, and histopathological assessments. Our results showed that cyclophosphamide induced obvious liver toxicity as marked by an increase in serum levels of alanine transaminase and aspartate transaminase, reduced serum albumin and total protein levels, in addition to histopathological changes. The malondialdehyde, tumor necrosis factor-α, and interleukin-6 levels were also elevated and total antioxidant capacity declined in serum and hepatic homogenates. Sitagliptin magnificently attenuated the cylophosphamide-induced histological alterations, improved liver function tests, enhanced total antioxidant capacity, and decreased malondialdehyde, tumor necrosis factor-α, and interleukin-6 in the blood and hepatic tissues. These findings suggest that sitagliptin has hepatoprotective activity against cyclophosphamide toxicity, which may be due to its antioxidant and anti-inflammatory effects.

Hepatoprotective efficacy of Lagenaria siceraria seeds oil against experimentally carbon tetrachloride-induced toxicity.

The liver is crucial for maintaining normal metabolism in the body. Various substances, such as toxic chemicals, drugs, and alcohol, can damage hepatocyte cells, leading to metabolic imbalances. The experiment aimed to determine the efficacy of Lagenaria siceraria seed oil (LSS) as a hepatoprotective agent against acute hepatotoxicity triggered by carbon tetrachloride (CCl4). A total of 20 rats were randomly separated into four groups. The control group: rats received 2 ml of distilled water orally, followed by 1.25 ml of olive oil intraperitoneally (i.p.) after 30 minutes. CCL4 group: rats were given a single intraperitoneal dose of 1.25 ml/kg b.w. of CCl4 in a 1:1 mixture with olive oil. Silymarin group: received 100 mg of silymarin per kg of b.w. diluted in 2 ml of distilled water orally, followed by CCl4 treatment after 30 minutes. LSS oil group: received LSS oil at 3g/kg b.w. orally, followed by CCl4 treatment after 30 minutes. Blood samples were collected to assess liver enzymes (AST, ALT, and ALP), proteins and bilirubin fractions, and redox status (catalase, reduced glutathione (GSH), and malondialdehyde (MDA)) were assessed in hepatic tissues. Changes in liver histopathological examination were also evaluated. In CCl4-treated rats, there was a significant increase in serum liver marker enzyme activity (ALP, AST, and ALT) along with a significant elevation (p < 0.05) in total bilirubin, indirect bilirubin, and direct bilirubin compared to the control rats. However, all these parameters decreased in the CCl4+ Silymarin and CCl4+LSS groups compared to CCl4-treated rats. There was a significant decline in total protein level and serum albumin in all experimental groups compared to the control, while globulin levels significantly increased in all experimental groups. There was a significant (p < 0.05) reduction in the level of GSH and catalase, with an increase in MDA level in CCl4 rats compared to other rats. Histopathological investigation of the LSS-treated group showed a hepatoprotective effect against CCl4. The study revealed that LSS oil has antioxidant activity against CCl4-induced toxicity.

Hepatotoxicidade do Cestrum axillare em bovinos do Distrito Federal, Goiás e Minas Gerais

ABSTRACT: This study reports four outbreaks of Cestrum axillare poisoning in cattle. Outbreaks occurred in farms of the Distrito Federal, Goiás, and Minas Gerais states during the dry season, affecting cows and heifers, with a mortality rate of 1 to 14,28%. Poisoned animals showed neurological signs and recumbency, followed by death within 12 hours, and some animals were found dead. Gross and histological lesions were typical of acute hepatotoxicity with hepatomegaly, enhancement of lobular pattern, and centrilobular to massive necrosis. This study seems to be the first report on C. axillare poisoning in cattle in the Distrito Federal, Goiás, and Triângulo Mineiro. C. axillare poisoning must be included in the differential diagnosis for cattle with hepatic necrosis in these locations.

Serine synthesis via reversed SHMT2 activity drives glycine depletion and acetaminophen hepatotoxicity in MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of the global population. Understanding the metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative stress, enhancing acute hepatotoxicity. Glycine supplementation or hepatocyte-specific ablation of the mitochondrial SHMT2 isoform in mice with hepatic steatosis mitigated acetaminophen-induced hepatotoxicity by supporting de novo glutathione synthesis. Thus, early metabolic changes in MASLD that limit glycine availability sensitize mice to xenobiotics even at the reversible stage of this disease.

Ameliorative effects of umbelliferone against acetaminophen-induced hepatic oxidative stress and inflammation in mice.

Acetaminophen (APAP) is a commonly used antipyretic and pain reliever that its overdose causes acute liver toxicity. Umbelliferone (UMB) has many pharmacological effects. In this study, the hepatoprotective effect of UMB on acute hepatotoxicity induced by APAP was investigated. Forty-nine male mice were separated into seven groups. The control received vehicle (i.p.), UMB group received UMB (120 mg/kg, i.p.), APAP group was treated with a single dose of APAP (350 mg/kg, i.p.), and pretreated groups received N-acetylcysteine (NAC, 200 mg/kg, i.p.) or different doses of UMB (30, 60, and 120 mg/kg, i.p.), respectively before APAP. Twenty-four hours after APAP injection, mice were sacrificed and blood and liver samples were collected. Then, serum and tissue samples were investigated for biochemical and histological studies. A single dose of APAP caused elevation in the serum liver enzymes, including alanine aminotransferase, aspartate transaminase, and alkaline phosphatase. The amounts of thiobarbituric acid reactive substances, tumor necrosis factor-alpha, and nitric oxide increased in the mice's liver tissue. Moreover, the amount of total thiol and the activity of antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) significantly diminished in the APAP group. Histological results confirmed the hepatotoxicity induced by APAP. However, UMB (more effective at 60 and 120 mg/kg) lessened APAP-induced hepatic injuries, which is comparable with NAC effects. The findings of this study provided evidence that UMB ameliorates liver injury induced by APAP through its antioxidant and anti-inflammatory effects.

Therapeutic potentials of N-acetylcysteine immobilized polyrhodanine nanoparticles toward acetaminophen-induced acute hepatotoxicity in rat.

N-acetylcysteine (NAC) is a recommended drug for treating acetaminophen (APAP) intoxication. Due to NAC's low bioavailability, this study aimed to use polyrhodanine (PR) nanoparticles (NPs) as a drug carrier to improve the effectiveness of NAC. After preparation and characterization of NAC loaded on PR, 30 rats were randomly divided into five groups of six. The first group (control) received normal saline. Groups 2-5 were treated with normal saline, PR, NAC, and NAC loaded on PR, respectively. The treatments were started 4 h after oral administration of APAP (2000 mg kg-1 ). After 48 h, the animals were anesthetized, and liver function indices and oxidative stress were measured in tissue and serum samples. The APAP administration can increase aminotransferases and alkaline phosphatase enzymes in serum, decreasing the total antioxidant capacity and thiol groups and increasing lipid peroxidation in liver tissue. Administration of PR-NAC could effectively improve the level of serum-hepatic enzymes, total antioxidant capacity and thiol groups, lipid peroxidation, and pathological changes in liver tissue in animals poisoned with APAP. PR-NAC has a significant therapeutic effect on preventing acute hepatotoxicity caused by APAP, and its effectiveness can be associated with an improvement in the oxidant/antioxidant balance of liver tissue.