Search Results (607)

Linezolid, an antimicrobial agent, has been linked to lactic acidosis, oxidative stress, and liver damage. Oxidative stress is considered to play a key role in this damage. Thiamine pyrophosphate (TPP), the active form of thiamine, may prevent lactate accumulation and enhance aerobic capacity. Therefore, this study aimed to evaluate the protective effect of TPP against possible linezolid-induced liver damage and lactic acidosis in rats. Twenty-four male Wistar albino rats were randomly assigned to four groups (n = 6): healthy control (HG), linezolid (LZD), thiamine plus linezolid (TLZD), and TPP plus linezolid (TPLZD). Thiamine and TPP (20 mg/kg, intraperitoneal (i.p.)) were administered once daily, while linezolid (125 mg/kg, per os (p.o.)) was given twice daily (250 mg/kg/day) for 28 days. Animals were euthanized under high-dose anesthesia (with 50 mg/kg, i.p. thiopental sodium). Liver tissues were analyzed for MDA, tGSH, SOD, and CAT, and examined histopathologically. Blood samples were collected prior to euthanasia to assess lactate, LDH, ALT, AST, and TPP levels. In the LZD group, MDA, lactate, ALT, AST, and LDH levels significantly increased, while tGSH, SOD, CAT, and TPP decreased (p < 0.001). Histopathology showed hydropic degeneration, necrosis, and mononuclear cell infiltration (p < 0.05). Thiamine did not prevent these alterations (p > 0.05), whereas TPP significantly prevented both biochemical and histopathological changes (p < 0.05), indicating its protective efficacy. TPP may offer significant protection against linezolid-induced hepatotoxicity and lactic acidosis. Full article

Background/Objectives: Thiamethoxam (TMX) is one of the most extensively utilized insecticides of the neonicotinoid family; however, its application is associated with notable toxic effects on multiple organs of mammals. Our purpose was to explore the potential hepatoprotective effect of taurine (TAU) and/or gallic acid (GA) against TMX-induced liver damage, with an emphasis on their role in regulating SIRT-1/PGC-1α, NF-κB/iNOS, and p53/Bax/caspase-3 pathways. Methods: Rats were assigned to seven groups (n = 6) and gavaged daily for 28 days with saline (control group), TAU at 50 mg/kg, GA at 20 mg/kg, TMX at 78.15 mg/kg, TMX + TAU, TMX + GA, and TMX + TAU + GA. Results: The findings revealed that TAU and/or GA attenuated TMX-induced liver injury, as demonstrated by the restoration of hepatic performance hallmarks and histological structure. TAU and GA mitigated TMX-mediated oxidative stress and boosted the antioxidant defense mechanism by upregulating the transcription levels of SIRT-1, PGC-1α, Nrf2, and HO-1. Moreover, TAU and GA suppressed TMX-associated inflammatory response by increasing IL-10 concentration and lowering the levels of NF-κB, IL-1β, and iNOS; the mRNA levels of NLRP3; and TNF-α immunoexpression. Both compounds, individually or concurrently, exerted an anti-apoptotic effect in TMX-treated rats, evidenced by increased Bcl-2 expression and reduced p53 mRNA level, Bax expression, and caspase-3 concentration. Conclusions: TAU and/or GA may be regarded as promising remedies that can alleviate TMX-induced hepatotoxicity by activating SIRT-1/PGC-1α signaling and abolishing inflammation and apoptosis. Full article

Background/Objectives: The liver, the body’s primary detoxifying organ, is often affected by various inflammatory diseases, including hepatitis, cirrhosis, and non-alcoholic fatty liver disease (NAFLD), many of which can be exacerbated by secondary infections such as spontaneous bacterial peritonitis, bacteremia, and sepsis—particularly in patients with advanced liver dysfunction. The global rise in these conditions underscores the need for effective interventions. Natural products have attracted attention for their potential to support liver health, particularly through synergistic combinations of plant extracts. Epavin, a dietary supplement from Erbenobili S.r.l., formulated with plant extracts like Taraxacum officinale (L.), Silybum marianum (L.) Gaertn., and Cynara scolymus (L.), known for their liver-supporting properties, has been proposed as adjuvant for liver functions. The aim of this work was to evaluate of Epavin’s antioxidant, anti-inflammatory, and protective effects against heavy metal-induced toxicity. In addition, the antibacterial effect of Epavin against a panel of bacterial strains responsible for infections associated with liver injuries has been evaluated. Methods: The protection against oxidative stress induced by H₂O₂ was evaluated in HepG2 and BALB/3T3 cells using the dichlorofluorescein diacetate (DCFH-DA) assay. Its anti-inflammatory activity was investigated by measuring the reduction in nitric oxide (NO) production in LPS-stimulated RAW 264.7 macrophages using the Griess assay. Additionally, the cytoprotecting of Epavin against heavy metal-induced toxicity and oxidative stress were evaluated in HepG2 cells using the [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide] (MTT) and DCFH-DA assays. The antibacterial activity of Epavin was assessed by determining the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) against Gram-positive (Enterococcus faecalis ATCC 29212, and BS, Staphylococcus aureus 25923, 29213, 43300, and BS) and Gram-negative (Escherichia coli 25922, and BS, Klebsiella pneumoniae 13883, 70063, and BS) bacterial strains using the microdilution method in broth, following the Clinical and Laboratory Standards Institute’s (CLSI) guidelines. Results: Epavin effectively reduced oxidative stress in HepG2 and BALB/3T3 cells and decreased NO production in LPS-stimulated RAW 264.7 macrophages. Moreover, Epavin demonstrated a protective effect against heavy metal-induced toxicity and oxidative damage in HepG2 cells. Finally, it exhibited significant antibacterial activity against both Gram-positive and Gram-negative bacterial strains, with MIC values ranging from 1.5 to 6.0 mg/mL. Conclusions: The interesting results obtained suggest that Epavin may serve as a valuable natural adjuvant for liver health by enhancing detoxification processes, reducing inflammation, and exerting antibacterial effects that could be beneficial in the context of liver-associated infections. Full article

The present study aimed to evaluate the therapeutic benefits of a hybrid material based on gold nanoparticles and natural extracts on an experimental model of thioacetamide-induced (TAA) liver injury in rats. The nanomaterials were synthesized using a green method, with Cornus sanguinea L. extract as a reducing and capping agent (NPCS), and were then mixed with Vaccinium myrtillus L. (VL) extract in order to achieve a final mixture with enhanced properties (NPCS-VL). NPCSs were characterized using UV–vis spectrophotometry and transmission electron microscopy (TEM), which demonstrated the formation of spherical, stable gold nanoparticles with an average diameter of 20 nm. NPCS-VL’s hepatoprotective effects were evaluated through an analysis of oxidative stress, inflammation, hepatic cytolysis, histology assays, and TEM in comparison to silymarin on an animal model of thioacetamide (TAA)-induced toxic hepatitis. TAA administration determined hepatotoxicity, as it triggered redox imbalance, increased proinflammatory cytokine levels and alanine aminotransferase (ALAT) activity, and induced morphological and ultrastructural changes characteristic of liver fibrosis. In rats treated with NPCS-VL, all these pathological processes were attenuated, suggesting a potential antifibrotic effect of this hybrid bionanomaterial. Full article

Background: Fructus Meliae Toosendan (FMT) is a traditional Chinese medicine used to treat ascariasis; however, its reported hepatotoxicity limits its application. Toosendanin (TSN), as a principal active component, is recognized as the primary toxic ingredient responsible for FMT-induced hepatotoxicity, but the underlying mechanisms remain elusive. Methods: HepG2 cells were treated with TSN and analyzed using Western blotting and qPCR assays for related gene transcription and protein expression. Lipid peroxidation and ferroptosis markers were measured. Balb/c and C57BL/6 mice received various doses of TSN administration, and their liver function was assessed with serum biochemistry and histopathology. Network pharmacology and oxidative lipidomics were performed to identify key targets and metabolites. Results: TSN triggered ferroptosis both in vitro and in vivo, accompanied by the elevated expression of 5-lipoxygenase (ALOX5) and its downstream metabolites. The ALOX5 level modulated hepatocyte sensitivity to TSN-induced ferroptotic damage. An ALOX5 knockdown alleviated TSN-induced liver injury and ferroptosis in vivo. Conclusions: Our study demonstrated that TSN induces hepatotoxicity by facilitating ALOX5-mediated lipid peroxidation, thereby sensitizing cells to ferroptosis. Full article

This study systematically reviews the non-traditional pharmacological effects of diclofenac, a well-known nonsteroidal anti-inflammatory drug, to explore its potential for drug repositioning beyond its established analgesic and anti-inflammatory applications. A comprehensive literature search was conducted using the PubMed, Scopus and Web of Science databases, covering studies from 1981 to 2025. It was revealed that over 94% of records in Scopus and Web of Science are duplicated in PubMed, so the latter was used for the search in our study. After duplicate removal and independent screening, 89 from 1123 retrieved studies were selected for the search. The analysis revealed a broad spectrum of diclofenac’s non-traditional pharmacological activities, including neuroprotective, antiamyloid, anticancer, antiviral, immunomodulatory, antibacterial, antifungal, anticonvulsant, radioprotective, and antioxidant properties, primarily identified through preclinical In vitro and In vivo studies. These effects are mediated through diverse molecular pathways beyond cyclooxygenase inhibition, such as modulation of neurotransmitter release, apoptosis, and cellular proliferation. Diclofenac showed potential for repositioning in oncology, neurodegenerative disorders, infectious diseases, and immune-mediated conditions. Its hepatotoxicity and cardiovascular risks necessitate strategies like advanced drug formulations, dose optimization, and personalized medicine to enhance safety. Large-scale randomized clinical trials are essential to validate these findings and ensure safe therapeutic expansion. Full article

HMG-CoA reductase inhibitors, statins, are extensively used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic disorders. However, one of the common side effects of statin therapy is a mild elevation in liver aminotransferases, observed in less than 3% of patients. Atorvastatin and simvastatin, in particular, are most frequently associated with statin-induced liver injury, leading to treatment discontinuation. Recent research has highlighted the antioxidant and anti-inflammatory properties of glucagon-like peptide-1 receptor (GLP-1R) activation in protecting against liver injury. Nonetheless, the potential protective effects of liraglutide (LIRA), a GLP-1R agonist, against atorvastatin (ATO)-induced liver dysfunction have not been fully elucidated. In this context, the present study aimed to investigate the protective role of LIRA in mitigating ATO-induced liver injury in rats, offering new insights into managing statin-associated hepatotoxicity. Indeed, LIRA treatment improved liver function enzymes and attenuated histopathological alterations. LIRA treatment enhanced antioxidant defenses by increasing Nrf2 content and superoxide dismutase (SOD) activity, while reducing NADPH oxidase. Additionally, LIRA suppressed inflammation by downregulating the HMGB1/TLR-4/RAGE axis and inhibiting the protein expression of pY323-MAPK p38 and pS635-NFκB p65 content resulting in decreased proinflammatory cytokines (TNF-α and IL-1β). Furthermore, LIRA upregulated GLP-1R gene expression and promoted autophagic influx via the activation of the pS473-Akt/pS486-AMPK/pS758-ULK1/Beclin-1 signaling cascade, along with inhibiting apoptosis by reducing caspase-3 content. In conclusion, LIRA attenuated ATO-induced oxidative stress and inflammation via activation of the Nrf-2/SOD cascade and inhibition of the HMGB1/TLR-4/RAGE /MAPK p38/NFκB p65 axis. In parallel, LIRA stimulated autophagy via the AMPK/ULK1/Beclin-1 axis and suppressed apoptosis, thus restoring the balance between autophagy and apoptosis. Full article

Liver injury caused by the irrational use of acetaminophen (APAP) represents a significant challenge in the field of public health. In clinical treatment, apart from N—acetylcysteine (NAC), the only approved antidote, there are extremely limited effective intervention measures for APAP-induced hepatotoxicity. Therefore, exploring novel liver-protecting drugs and elucidating their mechanisms of action is of great scientific significance and clinical value. Rosmarinic acid (RA), as a natural polyphenolic compound, has been proven to have significant antioxidant activity. Previous studies have shown that it has a protective effect against drug-induced liver injury. Nevertheless, the precise protective mechanism of RA in APAP-induced acute liver injury (AILI) has not been fully defined. This study was based on an AILI mouse model to systematically explore the liver-protecting effect of RA and its underlying molecular mechanisms. The research results showed that pretreatment with RA could notably mitigate liver pathological injury. It could decrease the activities of ALT and AST in the serum, suppress the liver inflammatory reaction, and reverse the decline in the levels of CAT, T-AOC, SOD, and GSH caused by APAP. Meanwhile, RA could enhance antioxidant defense capabilities by activating the Keap1/Nrf2/HO-1 signaling pathway, regulate the xCT/GPX4 axis to inhibit lipid peroxidation, and thus block the process of ferroptosis. In conclusion, this study confirmed that RA exerts a protective effect against AILI by regulating the Keap1/Nrf2/HO-1 axis to enhance antioxidant capacity and inhibit ferroptosis through the xCT/GPX4 pathway. Our research provides a theoretical basis for RA as a potential therapeutic agent for APAP-induced liver injury. Full article

Wild edible mushrooms (WEMs) are a popular delicacy in Thailand, prized for their unique flavor, texture, and nutritional value. Despite their widespread consumption, there is limited scientific research on their chemical compositions, biological activities, and potential health benefits. To bridge this knowledge gap, a comprehensive study was conducted on sixteen WEM species from ten families—Polyporaceae, Pleurotaceae, Russulaceae, Marasmiaceae, Pluteaceae, Boletinellaceae, Diplocystaceae, Lyophyllaceae, Psathyrellaceae, and Auriculariaceae—commonly found in northern Thailand. The proximate composition varied significantly among the WEM species, particularly in crude protein (12–51% w/w), crude fiber (1–30% w/w), and glucans (4–25% w/w). Astraeus odoratus exhibited the highest phenolic content, while P. cf. portentosus demonstrated the most potent antioxidant activity. WEM extracts also displayed notable inhibitory effects on α-glucosidase (5.82–79.43%) and α-amylase (1.30–90.79%). All extracts induced antioxidant regulators of Nrf2 and NQO1, suggesting that WEMs can help protect cells from oxidative stress, environmental toxins, and xenobiotics from food. Importantly, all extracts maintained high cell viability (>80%), indicating their safety for consumption. Furthermore, the mushrooms demonstrated a strong ability to reduce hepatotoxicity in HepG2 cells induced by tert-butyl hydrogen peroxide, highlighting their potential in preventing liver damage. This study not only underscores the nutritional and health benefits of WEMs but also establishes a vital scientific foundation for future research on their health effects and in vivo applications. In turn, these findings could serve as a crucial resource for optimizing the use of WEMs in ethnic cuisines and strengthening claims regarding their functional food properties. Full article

Ferroptosis, a form of regulated cell death driven by lipid peroxidation, has been implicated in the pathogenesis of liver diseases. This study investigates the role of circRNA_1156 in neodymium nitrate (Nd(NO₃)₃)-induced hepatocyte ferroptosis. Our in vitro experiments revealed that exposure to Nd(NO₃)₃ (1.2 µM) significantly reduced the viability of AML12 hepatocytes (p < 0.01), increased levels of reactive oxygen species (ROS) and malondialdehyde (MDA) (p < 0.001), and depleted glutathione (GSH) (p < 0.001). However, overexpression of circRNA_1156 effectively reversed these effects and suppressed the expression of ACSL4 and PKCβII (p < 0.01). In our in vivo experiments, chronic exposure to Nd(NO₃)₃ (7–55 mg/kg for 180 days) induced hepatic iron deposition, mitochondrial damage, and activation of the ACSL4/PKCβII pathway (p < 0.01). These adverse effects were significantly ameliorated by circRNA_1156 overexpression (p < 0.05). Our findings identify circRNA_1156 as a novel inhibitor of Nd(NO₃)₃-induced ferroptosis via downregulation of the ACSL4/PKCβII pathway, providing valuable therapeutic insights for hepatotoxicity caused by rare earth element compounds. Full article

Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, plays a crucial role in acetaminophen (APAP)-induced hepatotoxicity. While 4-octyl itaconate (4-OI) demonstrates protective effects against APAP toxicity, its molecular mechanisms remain to be fully elucidated. Through an innovative integration of untargeted metabolomics and pathway analysis, we unveil a novel dual mechanism by which 4-OI prevents APAP-induced ferroptosis. We discovered that 4-OI stabilizes SLC7A11 through OTUB1-mediated deubiquitination, thereby restoring cystine import and glutathione (GSH) synthesis. In addition, 4-OI activates the Nrf2 pathway, orchestrating a comprehensive antioxidant response by upregulating the key proteins involved in both glutathione metabolism and iron homeostasis, including GPX4, FTH1, FTL1, and FPN1. This coordinated action effectively prevents the accumulation of toxic iron and lipid peroxides. Our findings not only elucidate the protective mechanisms of 4-OI but also establish it as a promising therapeutic candidate for ferroptosis-related diseases through its unique ability to simultaneously modulate the SLC7A11-GPX4 antioxidant axis and iron homeostasis. Full article

This study looked into the underlying mechanisms and causal relationship between alcoholic liver disease (ALD) and the blood metabolite uridine using a variety of analytical methods, such as Mendelian randomization and molecular dynamics simulations. We discovered uridine to be a possible hepatotoxic agent aggravating ALD by using Mendelian randomization (MR) analysis with genome-wide association study (GWAS) data from 1416 ALD cases and 217,376 controls, as well as with 1091 blood metabolites and 309 metabolite concentration ratios as exposure factors. According to network toxicology analysis, uridine interacts with important targets such as SRC, FYN, LYN, ADRB2, and GSK3B. The single-cell RNA sequencing analysis of ALD tissues revealed that SRC was upregulated in hepatocytes and activated hepatic stellate cells. Subsequently, we determined the stable binding between uridine and SRC through molecular docking and molecular dynamics simulation (RMSD = 1.5 ± 0.3 Å, binding energy < −5.0 kcal/mol). These targets were connected to tyrosine kinase activity, metabolic reprogramming, and GPCR signaling by Gene Ontology (GO) and KEGG studies. These findings elucidate uridine’s role in ALD progression via immunometabolic pathways, offering novel therapeutic targets for precision intervention. These findings highlight the necessity of systems biology frameworks in drug safety evaluation, particularly for metabolites with dual therapeutic and toxicological roles. Full article

Background and Purpose: Methotrexate (MTX) is a widely used therapeutic agent for inflammatory and malignant diseases; however, its prolonged use is associated with hepatotoxicity through mechanisms that remain inadequately understood. This study aims to elucidate these mechanisms and assess the hepatoprotective potential of indole-3-acetic acid (IAA). Methods: Rats were allocated into five groups: control (group 1), IAA-treated (group 2), MTX-treated (group 3), quercetin (QUR) + MTX (group 4), and IAA + MTX (group 5). Hepatic function was assessed through the evaluation of serum liver enzymes, oxidative stress, and inflammatory and apoptotic markers using biochemical, molecular, histopathological, and immunohistochemical analyses. Results: The MTX-treated group demonstrated a significant increase in hepatic oxidative stress, inflammation, and apoptotic markers. Co-administration of IAA or QUR with MTX markedly reduced malondialdehyde (MDA) levels, while enhancing glutathione (GSH) levels and superoxide dismutase (SOD) activity. Moreover, hepatic inflammatory markers, including TNF-α, IL-6, and IL-1β, were significantly decreased in the IAA- and QUR-treated groups. Immunohistochemical analysis further revealed a reduced expression of NF-κB, TLR4, and caspase-3 in hepatic tissues following QUR-MTX or IAA-MTX treatments. Conclusions: IAA exhibited hepatoprotective effects against MTX-induced liver injury, comparable to QUR, by modulating the TLR4/NF-κB/caspase-3 pathway. These findings highlight its potential clinical application in reducing MTX-associated hepatic complications. Full article

This research explored the role of aflatoxin oxidase CotA in mitigating aflatoxin B₁ (AFB₁)-induced hepatotoxicity in Japanese quails. A total of 225 female Japanese quails, aged two weeks, were randomly assigned to three dietary groups: a control diet, an AFB₁-contaminated diet, and an AFB₁-contaminated diet supplemented with aflatoxin oxidase CotA for three weeks. The results indicate that quails receiving the AFB₁-contaminated diet exhibited reduced body weight gain, pronounced vacuolar degeneration within hepatocytes, and inflammatory cell infiltration. Additionally, the AFB₁ group demonstrated an increased liver index and elevated serum liver enzyme activities (ALT, AST, and ALP). Supplementation with CotA improved body weight gain and conferred protection against AFB₁-induced liver injury. Furthermore, the addition of CotA significantly enhanced liver antioxidant enzyme activities (T-AOC, GST, GSH-Px, POD, and CAT), reduced hepatic H₂O₂ and MDA levels, and upregulated the mRNA expression levels of genes in the Nrf2 pathway in quails exposed to AFB₁. AFB₁ exposure led to lipid droplet accumulation in liver tissues and elevated serum TG and LDL-C levels. However, the introduction of CotA mitigated AFB₁-induced alterations in lipid metabolism. Furthermore, dietary supplementation with CotA inhibited AFB₁-induced hepatocyte apoptosis and decreased the mRNA expression of apoptosis-related genes, including Bax, caspase-9, and caspase-3. Notably, the AFB₁+CotA group exhibited a significant reduction in AFB₁ residues and AFB₁-DNA adducts in quail liver tissues compared to the AFB₁ group. These findings indicate that aflatoxin oxidase CotA holds promise as a feed additive to alleviate AFB₁-induced hepatotoxicity. Full article

Background/Objectives: Liver disease is one of the most common medical problems in the world. The pharmacological correction of these pathologies includes the use of drugs with antioxidant and hepatoprotective action, among which there are natural and synthetic sulfur-containing compounds. However, many of these drugs have side effects, and their application does not always correspond to approaches in evidence-based medicine. Therefore, today the urgent problem is the search for new effective substances with high metabolitotropic properties and high safety criteria. The aim of this work was an in-depth study of the hepatoprotective and antioxidant action of a new investigational pteridine-containing “lead-compound” (DCTP) under conditions of experimental tetrachloromethane hepatitis in rats in comparison with the reference drug “Thiotriazoline”. Methods: The hepatoprotective effect of the compound was studied using a model of acute tetrachloromethane (CCl₄) hepatitis in adult male Wistar rats. The levels of biochemical liver damage markers were estimated with spectrophotometric methods. Histological and immunohistochemical methods were used for the determination of hepatocyte damage. The statistical processing of data was performed using the nonparametric Wilcoxon–Mann–Whitney method. Results: The results of the studies showed that DCTP was superior to the reference drug Thiotriazoline in terms of its effect on the levels of AST, DC, Schiff bases, and carbonylated proteins, which are markers of oxidative (Nrf2) and inflammatory (Lipocalin-2) stress, as well as its effect on animal survival. The results were confirmed by histological examination data, which showed regeneration of the hepatocyte membrane structure; a reduction in infiltrative, destructive, and inflammatory process in the liver; a reduction in the cytolytic process; stabilization; and an increase in the functional activity of the liver due to the administration of the study drug. The pharmacological effects of the studied compound (DCTP) are probably associated with its structural similarity to tetrahydrofolic acid, which is an integral component of oxidation–reduction processes and a participant in the biosynthesis of nitrogenous bases of nucleotides and amino acids. The obtained data show the antioxidant and hepatoprotective properties of the studied “lead-compound” from the pteridinethione group (DCTP). Conclusions: It was shown that the studied substance DCTP significantly reduces acute hepatotoxic effects caused by CCl₄, as evidenced by the decrease in the level of lipid peroxidation and prooxidant markers, the normalization of liver biochemical markers, the regeneration of the liver architecture, the limitation of inflammatory effects, the decrease in Nrf2 and Lipocalin-2 markers, and the induction of liver antioxidant enzymes. Full article