Hepatotoxic Effects Research Articles

Palmitoleic Acid Inhibits Hepatotoxic Effects by Reducing Trimethylamine-N-Oxide (TMAO) Formation in High L-Carnitine-Treated Mice

Background/Objectives: This study investigated the effects of palmitoleic acid (POA) consumption on liver function, intestinal microbiota, and trimethylamine-N-oxide (TMAO) levels in the serum of mice treated with 3% L-carnitine drinking water. The purpose was to highlight the impact of POA on liver injury associated with high L-carnitine intake. Methods: A correlation analysis was carried out. The physiological and biochemical results showed that the administration of POA could alleviate liver injury induced by high L-carnitine ingestion, as reflected by a reduction in liver function indices (ALT, AST, AKP, and TBA activities) and modulation of antioxidant enzyme activities (SOD, GSH-Px, MDA, and RAHFR). The study also monitored the levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Additionally, to assess the impact of POA on intestinal microbiota, we conducted a 16S rRNA high-throughput sequencing analysis. Results: The findings indicated that POA administration resulted in lower levels of TMAO in treated mice. Furthermore, POA could regulate the composition of intestinal microbiota in L-carnitine mice, particularly affecting Bacteroides vulgatus, Parabacteroides distasonis, Alistipes shahii, Lachnospiraceae NK4A136 group, and Parasutterella secunda, which were closely related to liver injury. Conclusions: In summary, POA could repair liver damage caused by high intake of L-carnitine by regulating the distribution of intestinal flora and subsequently decreasing serum TMAO levels.

Protective effect of magnetic water against AlCl3-induced hepatotoxicity in rats

This study aimed to examine whether or not aluminum chloride (AlCl3)-induced hepatotoxicity might be mitigated using magnetic water (MW) in rats. This study involved 28 adult male rats randomly assigned into the following 4 groups (7 rats/group): normal control (Cnt), MW, AlCl3, and Al Cl3 + MW. The Cnt group orally received normal saline, the MW group drank MW ad libitum for 2 months, and the AlCl3 and AlCl3 + MW groups were orally administered AlCl3 (40 mg/kg b.w.) alone or in combination with MW for 2 months, respectively. MW reduced AlCl3 toxicity as proved at functional, molecular, and structural levels. Functionally, MW reduced serum levels of liver enzymes (ALT, AST, ALP, GGT), while increased total proteins, and albumin. MW also restored redox balance in the liver (lower MDA levels, higher activities of CAT and SOD enzymes, and upregulated expression of NrF2, HO-1, and GST genes. Molecularly, MW downregulated hepatic expression of the epigenetic (HDAC3), inflammatory (IL1β, TNFα, NFκβ), and endoplasmic reticulum stress (XBP1, BIP, CHOP) genes. Structurally, MW enhanced liver histology. With these results, we could conclude that MW has the potential to ameliorate the hepatotoxic effects of AlCl3 through targeting oxidative stress, inflammation, epigenesis, and endoplasmic reticulum stress.

Azithromycin induces liver injury in mice by targeting the AMPK/Nrf2 pathway

Background Azithromycin is an antibacterial and anti-inflammatory drug widely used for the treatment of various diseases, including those caused by atypical pathogens, bacterial or viral infections, chronic sinusitis, and bronchial asthma, particularly in pediatric patients. However, concerns have emerged regarding its hepatotoxicity and its precise mechanism of action remains unclear. Objective To investigate the molecular mechanisms responsible for azithromycin-induced acute liver injury to advance our understanding of the progression and pathogenesis of antibiotic-induced liver damage, and to improve prevention and treatment strategies. Materials and methods C57BL/6 mice, Nrf2-/- mice, and primary hepatocytes were used. Primary hepatocytes from mice were isolated using a two-step perfusion method and cultured in vitro via the ‘sandwich’ culture model. Results The exposure to azithromycin resulted in increased apoptosis and reactive oxygen species (ROS) levels. In mouse models, intraperitoneal administration of azithromycin at varying concentrations and time points substantially induced hepatic disarray, swelling, and dysfunction. Azithromycin markedly upregulated the mRNA and protein levels of phosphorylated adenosine-activated protein kinase (AMPK) while downregulating nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and NADPH: quinone oxidoreductase 1 (NQO-1). Moreover, HO-1 and NQO-1 protein levels remained largely unaffected in primary hepatocytes co-cultured with azithromycin in Nrf2-/- mice. Conclusions Our findings suggest that azithromycin-induced acute liver injury is mediated by suppression of Nrf2 activation and ROS production. This sheds light on the potential mechanisms involved in azithromycin-induced liver damage, underscoring the importance of exploring targeted interventions to mitigate the hepatotoxic effects.

Assessment of the conceivable inhibitory activity of pathogenic microorganisms extracted from seaweed using phytochemicals, antioxidants, and in-silico molecular dynamic simulation

Turbinaria ornata, Polycladia myrica, and Padina pavonica is a perennial Mediterranean-native seaweed that is commonly used for mass display. The principal aims of this reconnaissance were the isolation of various compounds from methanolic seaweeds extraction and screening the potential effect as antibacterial, and antioxidant. The micro-dilution method was used to measure antibacterial activity. Gas chromatography-mass spectrophotometry (GC. Mass) abused to analyze the chemical components of the methanolic seaweed extract. The existence of 19 secondary metabolites was discovered using GC–MS analysis: 8 different compounds for each seaweed's species. Among these bioactive compounds, 4 compounds from P. pavonica extract showed the binding affinity and ability to react with Beta-ketoacyl synthase (PDB ID 1EK4) of Escherichia coli. The phytocompounds' drug-like and poisonous characteristics were predicted. Auto Dock was used to examine the ligand receptor complexes' binding strength. T. ornate and P. pavonica had the highest activity against K. pneumonia, with 22.50 mm (0.78 µg/ml) and 22.23 mm (5.10 µg/ml) obtained, respectively. In a concentration-dependent manner, the extract components demonstrated substantial antioxidant activity. P. pavonica had the highest scavenging activity (78.00%, IC50 = 6.35 µg/ml), while ascorbic acid had a 96.45% scavenging impact. Because the chemicals bind to the Lipinski Ro5, they have drug-like characteristics. The compounds had no hepatotoxic effects. P. pavonica extract has the prospect of being used as a source of medicinal drug-like chemicals. The docking investigation found a strong correlation between the experimental results and the docking results. Finally, brown seaweed extract, particularly P. pavonica extract, demonstrated strong antibacterial, antioxidant, and free radical scavenging properties.

Design, synthesis, and pharmacological characterization of sulfonylurea-based NLRP3 inhibitors: Towards an effective therapeutic strategy for Alzheimer's disease

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that severely diminishes the quality of life for millions. The NLRP3 inflammasome, a critical mediator of inflammation, has emerged as a promising therapeutic target for AD. In this study, we report the development and optimization of a novel series of sulfonylurea-based NLRP3 inhibitors, with a focus on compound MC1 for the treatment of AD. Utilizing the co-crystal structure of MCC950 in complex with NLRP3 as a guide, we employed a hybrid approach of computer-aided drug design and traditional medicinal chemistry to perform two iterative optimization cycles. This strategy led to the synthesis and evaluation of 40 sulfonylurea derivatives, culminating in the identification of MC1 as the lead candidate. MC1 exhibited enhanced NLRP3 inhibitory activity and demonstrated high binding affinity to NLRP3, effectively blocking NLRP3 activation induced by diverse stimuli such as ATP and Nigericin, without perturbing upstream processes like reactive oxygen species (ROS) generation. In vivo experiments in AD mouse models revealed that MC1 significantly ameliorated cognitive deficits, surpassing the performance of MCC950. Importantly, MC1 showed no signs of hepatotoxicity or adverse effects on the central nervous system. These findings suggest that MC1 holds strong potential as a lead compound for further development in AD therapy, providing a new scaffold for NLRP3 inhibition with improved safety and efficacy profiles.

Hepatotoxicity induced by subacute exposure of Mancozeb and Arsenic in Wistar rats: Mitigating effect of quercetin and catechin

BackgroundWidespread use of Mancozeb (MZ) fungicide in endemic areas having high levels of arsenic (As+3) in the groundwater is likely to cause toxicosis in humans and animals. Therefore, the present study aimed to determine the hepatotoxic effect of MZ and As+3 interaction in Wistar rats and mitigating potential of quercetin and catechin on such toxicity. MethodsSixty adult rats were randomly divided into 10 groups of 6 animals each. Group I served as control and group II was exposed to MZ (800 mg kg-1, PO). Groups III, IV, and V were provided drinking water containing As+3 at the rate of 10, 50 and 100 µg L-1, respectively. Groups VI, VII, and VIII were given drinking water containing As+3 at 10, 50 and 100 µg L-1, respectively, along with MZ. Groups IX and X received drinking water contaminated with 100 µg L-1, As+3 and MZ along with quercetin or catechin (50 mg kg-1 each), respectively. ResultsSignificant (p <0.05) alterations in hepatic biomarkers in blood, liver antioxidant status and hepatic histoarchitecture were observed in animals treated with individual toxicants in a dose-dependent manner, however, such toxicity-induced changes were more severe in co-exposed rats. The administration of quercetin or catechin significantly mitigated the dual toxicant administration-driven changes in biochemical markers of hepatic damage, hepatic antioxidant profile and liver histomorphology. ConclusionsBoth quercetin and catechin proved beneficial in reducing toxicant-induced oxidation-mediated hepatic damage as demonstrated by alleviation in altered levels of determinants of hepatic biochemical and oxidative stress parameters in addition to restoration of toxicant-induced histological alterations of hepatic tissue.

Polyherbal Formulation Development, Evaluation and Pharmacological Screening for Hepatoprotective Activity.

The current research work investigates the hepatoprotective action of polyherbal formulation prepared from ethanolic extracts of Azadirachta indica A. Juss, Moringa oleifera Lam, Cymbopogon citrates (DC.) Stapf, Tinospora cordifolia (Thumb.) Miers, Ricinus communis L., against experimental hepatotoxicity. The World Health Organization (WHO) is promoting herbal remedies derived from traditional medicinal plants in several countries. The main goal of this investigation was to create and evaluate the polyherbal formulation to protect albino Wistar rats against the hepatotoxic effects of CCl4. Three potential suspensions, polyherbal formulations A, B, and C, were formulated by trituration method using ethanolic extracts of specific medicinal plant components with different sodium carboxy methyl cellulose concentrations 1, 1.5, and 2%, respectively and evaluated the same for both certain physiochemical parameters, including organoleptic characteristics, pH, viscosity, sedimentation volume, redispersibility, density, specific gravity, zeta potential, and accelerated stability studies for three months and for hepatoprotective activity also. Evaluation parameters for Polyherbal Formulation-C have shown good results that met the specifications, with pleasant texture and appearance. Along with other physiochemical qualities, like pH, viscosity, flow rate and sedimentation, were all unchanged and showed significant hepatoprotective effects by reducing elevated serum enzyme levels SGOT, SGPT, ALP, total and direct bilirubin. It was discovered that each quality control parameter in the polyherbal suspension C formulation was thoroughly adequate and improved the recovery from hepatotoxicity caused by CCl4. These findings suggest that the produced polyherbal suspension C (containing ethanolic extracts of A. indica A. Juss, M. oleifera Lam, C. citrates (DC.) Stapf, T. cordifolia (Thumb.) Miers, R. communis L. may be stable, secure, and effective for use and exhibited notable hepatoprotective effects, possibly resulting from the combined impact of all these extracts.

Resmethrin induces implantation failure by disrupting calcium homeostasis and forcing mitochondrial defects in porcine trophectoderm and uterine luminal epithelial cells

Resmethrin, a type I pyrethroid insecticide, is frequently used globally in residential and farmland areas to control pests. Owing to the repeated administration of resmethrin, and particularly because of its lipophilic nature, residues have been detected in various environments, crops, and livestock. Previous studies have shown the adverse effects of resmethrin, including neurotoxicity and hepatotoxicity. However, the toxic effects of resmethrin on the female reproductive system have rarely been investigated. In the present study, we used two cell types, porcine trophectoderm (pTr) and porcine uterine luminal epithelial (pLE) cells, to examine the toxic effects of resmethrin on implantation and its mechanisms. Our study showed that resmethrin exposure induced apoptosis and inhibited cell cycle progression, thereby reducing the viability of both cell types. In addition, calcium homeostasis was disrupted following resmethrin treatment, and disrupted calcium homeostasis impaired the mitochondrial membrane potential and mitochondrial respiration. In addition to mitochondrial dysfunction, GRP75 and ER stress–related proteins were upregulated. Furthermore, the AKT and MAPK cascades were altered, and reactive oxygen species production and inflammation occurred after resmethrin treatment. Ultimately, through various mechanisms, resmethrin decreased the migratory abilities, and it could diminish the crosstalk between the two cell lines and lower the probability of successful implantation. Overall, we demonstrated that resmethrin interfered with the implantation process by triggering various toxic mechanisms. This study presents, for the first time, evidence regarding the mechanisms through which resmethrin exerts toxic effects on the female reproductive system, thereby raising awareness regarding the potential implications of its widespread use.

Assessment of Antioxidant and Hepatoprotective Effects of Kappaphycus alvarezii (Doty) Doty ex Silva Against Carbon Tetrachloride-Induced Liver Injury in Rats

Kappaphycus alvarezii (Doty) Doty ex Silva, commonly known as red algae, holds economic significance as a primary source of κ-carrageenan, which exhibits promising medicinal and therapeutic properties. This study aims to assess the antioxidant potential as well as hepatoprotective activity of the ethanolic extract of K. alvarezii (EEKA). The assays utilised to determine the antioxidant properties of EEKA were total phenolic content (TPC) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging. In addition, the ability of EEKA to ameliorate experimentally induced liver injury in Sprague-Dawley rats caused by carbon tetrachloride (CCl4) was evaluated. The biochemical assays involved measuring liver marker enzymes (AST and ALT) in serum as well as determining the levels of reduced glutathione (GSH), lipid peroxidation (LPO) via malondialdehyde, catalase (CAT), and glutathione S-transferase (GST) in liver homogenates. The TPC and DPPH radical scavenging activity of EEKA demonstrated relatively low antioxidant properties compared to standard references. However, CCl4-induced groups exhibited significantly increased levels of AST and ALT, along with depletion of antioxidant status (GSH, CAT, and GST) indicated by LPO. Pretreatment with EEKA resulted in slightly decreased liver marker enzyme activity and LPO, coupled with an increase in antioxidant status. These findings suggest that EEKA contains active principles capable of counteracting the hepatotoxic effects induced by CCl4.

Computational Screening of FDA‐Approved Hepatitis C Drugs for Inhibition of VEGFR2 in Liver Cancer

AbstractLiver cancer (LC) is one of the most common tumours and the leading cause of cancer‐related death globally. Amidst the problems associated with existing treatments, such as hepatotoxicity, recurrence, drug resistance, and other adverse effects, researchers are under pressure to find alternatives. Towards a comprehensive rationalisation of the search for new anti‐LC drugs among approved ones, we employed an in‐silico approach to accelerate the selection of the most efficacious LC drugs. The FDA‐approved hepatitis C virus (HCV) drugs were docked with the LC protein using the AutoDock Vina software. Compared to the control compound, two FDA‐approved HCV drugs (DB09102 and DB09027) were selected based on their binding energies and interactions with the target protein, which showed comparable binding energies. Furthermore, these compounds were then subjected to molecular dynamic simulation, principle component analysis, and MMGBSA using the AMBER20 software, and the results showed stable complexes compared to the control complex. All things considered, this study will help the scientific community and society find a novel drug to treat LC.

Putative role of 6-chogaol against tramadol-induced hepatotoxicity in albino rats via anti-inflammatory, antifibrotic, and antiapoptotic effects

Tramadol is a commonly used drug to relieve pain and avoid premature ejaculation in males with hepatotoxic effects, and 6-chogaol has potent anti-inflammatory and hepatoprotective properties.The work impetus is probing the hepatoprotective mechanisms of 6-chogaol against tramadol hepatoxicity. Twenty adult male rats were enrolled to obtain four equal groups [control group (G1), 6-chogaol group (G2), tramadol group (G3), and 6-chogaol+tramadol group (G4)]. Liver specimens were excised and processed to evaluate hepatocyte injury through histopathological (HP), immunohistochemical (IHC), flow cytometry, and biochemical investigations. The HP study exhibited hepatic injury in G3 hepatocytes (inflammatory cell infiltration, hepatic fibrosis, and disturbed liver structure). The IHC study showed a significant rise in caspase-3 and reduced PCNA immuno-expression (IE). Likewise, the flow cytometry and biochemical experiments exhibited a substantial elevation of apoptotic hepatocytes and the serum levels of IL-1β, IL-6, TNF-α, ALP, ALT, and AST in G3. In contrast, G4 rats significantly improved in all HP, IHC, flow cytometry, and biochemical parameters. Collectively, tramadol intake exerted harmful toxic effects on hepatocytes, whereas 6-Shogaol hampered these changes and served as a natural hepatoprotective agent. Therefore, we advise concurrent intake of 6-Shogaol supplement with tramadol to preserve the integrity of hepatic tissues.

Exploring Cannabis sativa L for Anti-Alzheimer Potential: An Extensive Computational Study including Molecular Docking, Molecular Dynamics, and ADMET Assessments

Introduction: Cholinesterase enzymes play a pivotal role in hydrolyzing acetylcholine, a neurotransmitter crucial for memory and cognition, into its components, acetic acid, and choline. A primary approach in addressing Alzheimer's disease symptoms is by inhibiting the action of these enzymes. Method: With this context, our study embarked on a mission to pinpoint potential Cholinesterase (ChE) inhibitors using a comprehensive computational methodology. A total of 49 phytoconstituents derived from Cannabis sativa L underwent in silico screening via molecular docking, pharmacokinetic and pharmacotoxicological analysis, to evaluate their ability to inhibit cholinesterase enzymes. Out of these, two specific compounds, namely tetrahydrocannabivarin and Δ-9- tetrahydrocannabinol, belonging to cannabinoids, stood out as prospective therapeutic agents against Alzheimer's due to their potential as cholinesterase inhibitors. These candidates showcased commendable binding affinities with the cholinesterase enzymes, highlighting their interaction with essential enzymatic residues. objective: Our study aims to pinpoint potential Cholinesterase (ChE) inhibitors derived from Cannabis sativa L using molecular docking, pharmacokinetic, and pharmacotoxicological analysis. Result: They were predicted to exhibit greater binding affinities than Rivastigmine and Galantamine. Their ADMET assessments further classified them as viable oral pharmaceutical drugs. They are not expected to induce any mutagenic or hepatotoxic effects and cannot produce skin sensitization. In addition, these phytoconstituents are predicted to be BBB permeable and can reach the central nervous system (CNS) and exert their therapeutic effects. To delve deeper, we explored molecular dynamics (MD) simulations to examine the stability of the complex formed between the best candidate (Δ-9-tetrahydrocannabinol) and the target proteins under simulated biological conditions. The MD study affirmed that the ligand-ChE recognition is a spontaneous reaction leading to stable complexes Conclusion: Our research outcomes provide valuable insights, offering a clear direction for the pharmaceutical sector in the pursuit of effective anti-Alzheimer treatments.

Glycidol-induced hepatocyte apoptosis via endoplasmic reticulum stress: The underlying role of the gut-liver axis

Glycidol (CAS: 556-52-5), a known carcinogen and genotoxicant, is often found in refined vegetable oils. Human exposure predominantly occurs through consumption of these oils and their byproducts, which contain glycidyl esters (GEs). Upon ingestion, GEs are metabolized to release glycidol, posing substantial health hazards. Historical studies have reported the tumorigenic properties of glycidol across various organs in mice models, encompassing the stomach, liver, lungs, brain, mammary gland, and skin. In this study, we employed a Balb/c mice model to investigate the hepatotoxic effects of glycidol following exposure to escalating doses (0, 25, 50, and 100 mg/kg bw/day). The hepatotoxicity was evidenced by a significant elevation in liver enzymes (ALT, AST), indicative of liver cell damage. Furthermore, biochemical analysis revealed heightened levels of oxidative stress indicators (SOD, MDA, GSH) and the upregulation of endoplasmic reticulum stress proteins, underscoring the cellular stress response. The induction of hepatocyte apoptosis served as a direct marker of liver damage caused by glycidol exposure. Additionally, glycidol altered the composition of intestinal microbiota and short-chain fatty acids (SCFAs), which unbalanced homeostasis. Gut barrier integrity markers (ZO-1, Claudin-1, Occludin, TLR4, LPS) indicated increased permeability of harmful substances to the liver via the gut-liver axis, which exacerbated hepatic injury. These findings highlight glycidol's disruption of gut homeostasis and its hepatotoxic potential.

Effect of cannabidiol and hemp extract on viability and function of hepatocytes derived from human induced pluripotent stem cells

Since the passage of the 2018 Agriculture Improvement Act (2018 Farm Bill), the number of products containing cannabis-derived compounds available to consumers have rapidly increased. Potential effects on liver function as a result from consumption of products containing cannabidiol (CBD), including hemp extracts, have been observed but the mechanisms for the effects are not fully understood. In this study, hepatocytes derived from human induced pluripotent stem cells (iPSCs) were used to evaluate potential hepatic effects of CBD and hemp extract at exposure concentrations ranging from 0.1 to 30 μM. Despite that a significant reduction in cell viability occurred only in the 30 μM group for both CBD and hemp extract, significant changes to cytochrome P450 activity, mitochondrial membrane potential, and lipid accumulation occurred within the concentration range of 0.1–3 μM for both CBD and hemp extract. Albumin and urea production, caspase 3/7 activity, and intracellular glutathione were significantly affected within the concentration range of 3–30 μM by CBD or hemp extract. These findings indicate that CBD and hemp extract can alter hepatic function and metabolism. The current study contributes data to help inform the evaluation of potential hepatotoxic effects of products containing cannabis-derived compounds.

Nephrotoxicity of Cylindrospermopsin (CYN) and Microcystin-LR (MC-LR) on Mammalian Kidney: Wistar Rat as a Model Assessment

Naturally derived cyanotoxins, cylindrospermopsin (CYN), and microcystin-LR (MC-LR) have shown hepatotoxic and nephrotoxic effects in several studies. The present study aimed to determine the possible nephrotoxicity of MC-LR and CYN on mammalian kidneys using male Wistar rats as an animal model. Potential nephrotoxicity was evaluated at different doses of CYN (0.175 μg.kg-1, 0.140 μg.kg-1, 0.105 μg.kg-1) and MC-LR (0.105 μg.kg-1, 0.070 μg.kg-1, 0.035 μg.kg-1) was observed. Water samples from dug wells contaminated with CYN (0.161 μg.kg-1) and MC-LR (0.091 μg.kg-1) from the Padaviya area in Anuradhapura, Sri Lanka were used as environmental samples. The control groups were treated with distilled water. The exposure time of rats to the toxin was 90 days. Evaluation of urinary creatinine, serum creatinine, and Kidney Injury Molecule-1 (KIM-1) were estimated using standard protocols. A significant increase in serum creatinine levels was observed in all CYN and MC-LR treated groups (p&lt;0.05) after 7 and 42 days of exposure, respectively, compared to control. It was found a decrease of urine creatinine when rats were treated with different concentrations of CYN and MC-LR (p&lt;0.05) after 7 days compared to the control. The highest KIM-1 concentrations were recorded at 0.175 μg.kg-1 of CYN and 0.105 μg.kg-1 of MC-LR. The concentrations of KIM-1 in the control groups for CYN-treated and MC-LR-treated were not detected. Luminal protein, nuclear pyknosis, mild tubular epithelial swelling, vascular congestion, and interstitial inflammation in CYN and MC-LR treated groups were common. No predominant changes were observed in the control groups treated with CYN and MC-LR. The results of the present study confirm that the consumption of CYN and MC-LR-contaminated water may lead to kidney injury in Wistar rats.

Dapagliflozin: A Promising Strategy to Combat Cisplatin-Induced Hepatotoxicity in Wistar Rats.

Recognizing the challenges posed by chemotherapy, specifically the hepatotoxic effects of drugs like cisplatin, this study aimed to examine the hepatoprotective potential of dapagliflozin to mitigate cisplatin-induced hepatotoxicity in a rat model. This study focused on repurposing drugs such as dapagliflozin and natural agents like silymarin as potential interventions to address cisplatin-induced hepatotoxicity. Thirty adult female Wistar rats were distributed into five groups and treated with cisplatin alone, silymarin, dapagliflozin, or a combination of dapagliflozin and silymarin accordingly for 45 days. Body weight, fasting blood glucose levels, liver function tests, and histopathological analysis were conducted to evaluate the hepatoprotective effects. Cisplatin-induced hepatotoxicity significantly (p < 0.05) increased the serum levels of ALT, AST, TB, and reduced the TP and albumin levels. Dapagliflozin administration led to significant reductions in ALT, AST, TB, and increased albumin levels. Silymarin demonstrated comparable effects. Combining dapagliflozin and silymarin showed synergistic effects, further reducing the liver enzymes and improving albumin levels. Histopathological examination supported these findings, revealing the restoration of liver structure with dapagliflozin and silymarin treatment. Dapagliflozin and silymarin exhibited substantial hepatoprotective benefits against cisplatin-induced hepatotoxicity in rats. The combination therapy demonstrated synergistic effects, highlighting a potential therapeutic approach for mitigating chemotherapy-induced liver damage. Further research into molecular mechanisms and clinical translation is warranted, offering hope for improved clinical outcomes in cancer patients undergoing cisplatin-based chemotherapy.

Zinc oxide nanoparticles cause hepatotoxicity in rare minnow (Gobiocypris rarus) via ROS-mediated oxidative stress and apoptosis activation and inhibition of lipid peroxidation

Zinc oxide nanoparticles (ZnO NPs) measuring 30 ± 10 nm in diameter are utilized in various applications, including batteries, plastics, ceramics, cosmetics, flame retardants, and food. However, their potential impact and risk on aquatic ecosystems remain unclear. This study examined the hepatotoxic effects of dietary ZnO NPs in rare minnow. Three hundred rare minnows were fed diets containing 0 mg/kg, 20 mg/kg and 60 mg/kg of ZnO NPs for 60 days, with hepatotoxicity assessments at 15-day intervals. The histological data showed that ZnO NPs severely damage liver tissues, causing cytoplasmic vacuolization and irregular or missing nuclei. The treatment groups showed a significant rise in the liver injury index (P < 0.05). Moreover, there was a notable increase in zinc accumulation in the ZnO NPs groups compared to the control group (P < 0.05). ZnO NPs also reduced body weight and hepato-somatic index (HSI) in rare minnows. The enzyme activity results showed elevated levels of reactive oxygen species (ROS), total cholesterol (T-CHO), triglyceride (TG), acetyl Coa carboxylase (ACC), and fatty acid synthase (FAS) in the ZnO NPs fed groups, while total antioxidant capacity (T-AOC) and malondialdehyde (MDA) decreased. Further investigation found that accumulation of ZnO NPs in the liver tissues up-regulated the levels of genes related to antioxidant (mn-sod, cat and nf-κb), pro-apoptotic (bax) and lipogenesis (gpat3, dgat1a and dgat1b), while down-regulating genes associated with lipid catabolism (cpt1 and tpi1). These findings suggest that dietary ZnO NPs cause hepatotoxicity by inducing oxidative stress through ROS, triggering apoptosis, and inhibiting lipid peroxidation. The results indicate that ZnO NPs may pose a significant threat to aquatic animals and ecosystems.

A Case Report : Tuberculosis Drug Induced Liver Injury: A Case Report

Tuberculosis is one of world health problem, especially in developing countries. Treatment regimen with multiple first-line anti-tuberculosis drugs (ATD) such as Isoniazid, Rifampicin, Pyrazinamide, Ethambutol, And Streptomycin remains the most effective for treatment of tuberculosis. Adverse drug reactions (ADRs) to antituberculosis drugs may range from mild gastrointestinal disturbances to serious hepatotoxicity, peripheral neuropathy, and cutaneous adverse effects. We report a 65 year old male patient with a complaint of yellowish discoloration of sclera, nausea and vomitting after three days of initiation of ATD theraphy. The patient has been diagnosed with Tuberculosis relaps and has been taking ATD since June 2024. Patient noted epigastric pain. Laboratory examination found an increase in bilirubin level and imbalance electrolyte. The treatment is in the form of discontinuation of ATD, supportive therapy and followed by hepatoprotective supplements. ATD should be discontinued in patients with hepatotoxicity and fixed drug eruption until liver function and clinical symptoms improve. Initiation of ATD administration is carried out by administering one by one regimen. The patient is currently experiencing antituberculosis drug-induced hepatotoxicity, which is managed by providing supportive care and different AT regimen was prescribed.

Impact of enniatins and beauvericin on lipid metabolism: Insights from a 3D HepaRG spheroid model

Emerging mycotoxins enniatins (ENNs) and beauvericin (BEA) pose potential health risks to humans through dietary exposure. However, research into their mechanisms of toxicity is limited, with a lack of comprehensive toxicological data. This study investigates from a hepatic lipid metabolism perspective, establishing a more precise and reliable 3D HepaRG hepatocyte spheroid model as an alternative for toxicity assessment. Utilizing physiological indices, histopathological analyses, lipidomics, and molecular docking techniques, it comprehensively elucidates the effects of ENNs and BEA on hepatic lipid homeostasis and their molecular toxicological mechanisms. Our findings indicate that ENNs and BEA impact cellular viability and biochemical functions, significantly altering lipid metabolism pathways, particularly those involving glycerophospholipids and sphingolipids. Molecular docking has demonstrated strong binding affinity of ENNs and BEA with key enzymes in lipid metabolism such as Peroxisome Proliferator-Activated Receptor α (PPARα) and Cytosolic Phospholipase A2 (cPLA2), revealing the mechanistic basis for their hepatotoxic effects and potential to impair liver function and human health. These insights enhance our understanding of the potential hepatotoxicity of such fungal toxins and lay a foundation for the assessment of their health risks.

Triazine herbicide prometryn alters epoxide hydrolase activity and increases cytochrome P450 metabolites in murine livers via lipidomic profiling

Oxylipins are a group of bioactive fatty acid metabolites generated via enzymatic oxygenation. They are notably involved in inflammation, pain, vascular tone, hemostasis, thrombosis, immunity, and coagulation. Oxylipins have become the focus of therapeutic intervention since they are implicated in many conditions, such as nonalcoholic fatty liver disease, cardiovascular disease, and aging. The liver plays a crucial role in lipid metabolism and distribution throughout the organism. Long-term exposure to pesticides is suspected to contribute to hepatic carcinogenesis via notable disruption of lipid metabolism. Prometryn is a methylthio-s-triazine herbicide used to control the growth of annual broadleaf and grass weeds in many cultivated plants. The amounts of prometryn documented in the environment, mainly waters, soil and plants used for human and domestic consumption are significantly high. Previous research revealed that prometryn decreased liver development during zebrafish embryogenesis. To understand the mechanisms by which prometryn could induce hepatotoxicity, the effect of prometryn (185 mg/kg every 48 h for seven days) was investigated on hepatic and plasma oxylipin levels in mice. Using an unbiased LC–MS/MS-based lipidomics approach, prometryn was found to alter oxylipins metabolites that are mainly derived from cytochrome P450 (CYP) and lipoxygenase (LOX) in both mice liver and plasma. Lipidomic analysis revealed that the hepatotoxic effects of prometryn are associated with increased epoxide hydrolase (EH) products, increased sEH and mEH enzymatic activities, and induction of oxidative stress. Furthermore, 9-HODE and 13-HODE levels were significantly increased in prometryn treated mice liver, suggesting increased levels of oxidation products. Together, these results support that sEH may be an important component of pesticide-induced liver toxicity.