Search Results (147)

Accumulating evidence indicates that acute, life-threatening acetaminophen (APAP) poisoning is associated with systemic inflammation (SI). Investigating SI in experimental models holds promise for the development of pathogenetic therapies. This study aimed to evaluate SI manifestations in a murine model of APAP-induced toxic liver injury. Ten-week-old male C57Bl/6 mice received a single intraperitoneal dose of 600 mg/kg APAP, corresponding to the median lethal dose (LD50). To assess signs of multiorgan damage and SI, we performed histological examinations of internal organs as well as immunoenzymatic, hematological, and biochemical analyses of blood samples. Histological analysis revealed tissue alterations in the liver, kidneys, spleen, lungs, and heart, accompanied by functional impairment. Statistically significant changes were observed in plasma levels of tumor necrosis factor-α (TNF-α), IL-1α, IL-6, IL-10, C-reactive protein (CRP), platelet count, total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, and troponin I. Severe liver damage induced by APAP was associated with a cytokine storm, coagulopathy (thrombocytopenia), systemic alterations, pulmonary edema, and multiorgan dysfunction. Collectively, these findings indicate that severe APAP-induced liver damage triggers SI as a characteristic pathological process. Full article

Biochar-supported rare earth oxides are herein assessed as heterogeneous catalysts for the UV-assisted Catalytic Wet Peroxide Oxidation (UV-CWPO) treatment of pharmaceuticals under mild conditions. Catalysts were synthesized by two different pyrolysis methods (activated carbon-assisted oxygen-limited pyrolysis in a muffle furnace, and inert-gas pyrolysis in a tubular furnace under nitrogen flow), and characterized by XRD, SEM, and N₂ adsorption–desorption isotherms. Their performance in assisting 385 nm UVA-LED CWPO treatment of acetaminophen (ACE), diclofenac (DCF), and metamizole (MTZ) was assessed under circumneutral pH conditions. The biochar-supported cerium-loaded catalyst prepared by oxygen-limited pyrolysis reported the highest activity, achieving 80% ACE and 70% DCF removals within 120 min of treatment, whereas MTZ was completely removed in less than 10 min, with only 16% of the removal attributable to adsorption. Superoxide radicals dominated the degradation mechanism, and photogenerated holes and hydroxyl radicals contributed moderately. Catalyst stability (minimal activity loss and negligible cerium leaching) was confirmed over five consecutive reuses. Degradation efficiency decreased ≈12–18% because of radical scavenging losses caused by the content of inorganic ions and organic matter in tap, river, and WWTP effluent waters. Treated effluents addressed lower toxicity than untreated solutions, reinforcing the environmental safety of this treatment strategy. Full article

Acetaminophen (APAP) represents a major cause of drug-induced liver injury (DILI), and effective pharmacological interventions remain limited. Annexin A5 (AnxA5), a Ca²⁺-dependent phospholipid-binding protein, participates in diverse biological processes related to tissue repair. In this study, we evaluated AnxA5 expression in APAP-challenged mouse livers and clinical samples from patients with liver injury. Using hepatic cell lines AML12 and HepG2, we performed overexpression-based functional assays to assess the cytoprotective effects of AnxA5 against APAP toxicity. Co-immunoprecipitation assays were applied to characterize protein interactions, and mitochondrial functional parameters were measured to dissect the underlying molecular mechanism. We found that AnxA5 was significantly upregulated in both APAP exposed mice and APAP DILI patients. Cellular functional assays showed that AnxA5 overexpression mitigated APAP triggered cytotoxicity in AML12 and HepG2 cells. Mechanistically, AnxA5 bound to voltage dependent anion channel 1 (VDAC1), restrained VDAC1 mediated mitochondrial Ca²⁺ influx, and suppressed VDAC1 oligomerization, which further inhibited mitochondrial permeability transition pore (mPTP) opening. In an APAP-induced liver injury mouse model, exogenous recombinant AnxA5 treatment maintained mitochondrial integrity and ameliorated hepatic inflammation and liver damage. Collectively, our data reveal AnxA5 as an endogenous mitochondrial protective factor and support its therapeutic potential against APAP-induced liver injury. Full article

Background: Although genetic-environmental interactions are established in autism spectrum disorder (ASD), how environmental toxicants confer susceptibility remains unclear. This study aimed to investigate potential relationship between genetically predicted cerebrospinal fluid (CSF), metabolite levels and ASD liability, and to prioritize regulatory genes, key pathways, and candidate environmental toxicants. Methods: Using two ASD GWAS datasets (exploration data: 18,381 ASD cases/27,969 controls; validation data: 18,235 ASD cases/36,741 controls), we applied multi-omics approaches to prioritize ASD-associated CSF metabolites, regulatory SNPs, and genes. Enrichment analysis and protein–protein interaction (PPI) network analysis were performed on these metabolite-related genes to explore the potential mechanisms linking CSF metabolic disturbances to ASD. Finally, candidate environmental neurotoxicants were screened through protein-chemical interaction analysis, with binding relationships assessed via molecular docking prediction. Results: Two-sample Mendelian randomization (MR) analysis prioritized adenine and proline as candidate CSF metabolites with potential risk associations with ASD. Summary-data-based MR (SMR) prioritized 39 brain-specific quantitative trait loci (QTL) involving 35 candidate regulatory genes, including dual-metabolite modulator GRM8. Functional enrichment analyses suggested potential associations with mitochondrial dysfunction, Hippo signaling pathway, and microtubule dynamics impairment, with protein–protein interaction networks highlighting KATNA1/KATNAL2 as hubs. Protein-chemical interaction screening nominated 14 candidate environmental toxicants, including established chemicals (acetaminophen, valproic acid, estradiol) and novel candidates (SB-431542, K 7174, benzo[a]pyrene), with docking affinity assessed computationally. Conclusions: Our study provides suggestive evidence that elevated adenine and proline may be potential risk factors for ASD and suggests possible involvement of the mitochondrial–Hippo–microtubule pathway. We also propose benzo[a]pyrene as a candidate environmental toxicant that may perturb CSF metabolism. However, given the limited statistical significance, these findings require further validation. Full article

Drug-induced liver injury (DILI) remains a major cause of acute liver failure and drug withdrawal from the market. Recently developed three-dimensional (3D) hepatic in vitro systems exhibit improved functionality and drug sensitivity compared with conventional two-dimensional cultures. These 3D models range from simple physiologic-like culture systems to advanced bioreactors with dynamic flow to provide sufficient nutrients and consistent drug exposure. However, whether dynamic perfusion improves sensitivity and reproducibility of hepatotoxicity testing remains unclear. Here, we developed a tailor-made perfusion platform to support volumetric bioprinted hepatic constructs for hepatotoxicity testing. The constructs consist of intrahepatic cholangiocyte organoids (ICOs) differentiated towards hepatocyte lineage and embedded in a gelatin methacryloyl bioresin. For toxicity evaluation, the hepatocyte-like ICO constructs were exposed to prolonged subtoxic acetaminophen treatment (10 mM, 7 days). The perfusion system effectively maintained and enhanced hepatocyte differentiation, evidenced by upregulated hepatic markers under perfused conditions compared to static controls. Testing of acetaminophen hepatotoxicity revealed that the perfused constructs displayed elevated cellular injury, with markedly higher liver injury markers relative to controls. Collectively, this study demonstrates the successful application of perfusion-based 3D model culture and highlights its potential as a more physiological platform for hepatotoxicity risk assessment in drug discovery and regenerative medicine. Full article

Background: Acute liver injury (ALI) is commonly caused by acetaminophen (APAP) overdose, which drives oxidative stress alongside activation of innate immune signaling. Casticin, a naturally occurring flavonoid, has anti-inflammatory and antioxidant properties. Focusing on the toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/tumor necrosis factor receptor-associated factor 6 (TRAF6)/nuclear factor kappa B (NF-κB) pathway, this study assessed casticin’s ability to protect mice from APAP-induced hepatotoxicity. Methods: APAP-induced ALI was established in mice randomly assigned to the following six groups: normal control, casticin control, APAP, APAP plus N-acetylcysteine (NAC), APAP plus low-dose casticin, and APAP plus high-dose casticin. Casticin was administered for three consecutive days before APAP to evaluate its preventive rather than therapeutic potential. Biochemical and histological analyses were performed, with molecular assessments using Western blotting, ELISA, quantitative real-time PCR (qPCR), and immunohistochemistry. Results: APAP significantly elevated serum ALT, AST, and ALP and markedly deteriorated hepatic architecture, confirming hepatotoxicity. APAP also induced lipid peroxidation and depleted antioxidant defenses. Hepatic TNF-α and IL-6 increased, IL-10 decreased, and the abundance of TLR4, MyD88, TRAF6, and NF-κB p65 was elevated. Casticin reduced these pathway components, lowered TNF-α and IL-6, and increased IL-10 dose-dependently, with effects approaching those of NAC. Conclusions: Casticin protected the liver against APAP toxicity, restraining oxidative injury while damping TLR4/MyD88/TRAF6/NF-κB signaling. Full article

Acetaminophen (paracetamol, APAP) is a widely used analgesic and antipyretic drug. Under normal physiological conditions, it does not directly interact with or disrupt cellular membranes. However, in cases of acetaminophen overdose or toxicity, severe cellular damage has been described, involving a broad spectrum of effects at different cellular levels. These toxic effects may involve membrane structures, including mitochondrial, plasma, and other intracellular membranes. Antimicrobial peptides (AMPs) are short, usually cationic and amphipathic peptides produced by both microorganisms and multicellular organisms, serving diverse defensive and competitive functions. In many cases, they exert their antimicrobial activity by direct interaction with bacterial or fungal membranes, leading to membrane destabilization and cell death. Owing to this membrane-targeting mechanism, AMPs may also interact with eukaryotic cell membranes, thereby exerting toxic or off-target effects under certain conditions. Here, we review the current knowledge on the membrane-related effects of acetaminophen toxicity and the mechanisms by which AMPs interact with biological membranes. In the event of combined exposure to acetaminophen and AMPs in therapeutic or experimental settings, the biological consequences remain unexplored. Such combined exposure may give rise to toxic effects and membrane-associated alterations. We further discuss potential mechanisms of interference, additive toxicity, and synergistic interactions between acetaminophen and AMPs, highlighting critical knowledge gaps and directions for future research. Full article

Paracetamol is a well-known analgesic drug. Studies linked gestational paracetamol use to disorders like autism and attention-deficit/hyperactivity disorder. This study aimed to evaluate the role of prenatal paracetamol exposure in 1-month-old offspring rats. Sixteen pregnant albino rats were divided into four groups: group I received saline; group II received sodium valproate 600 mg/kg i.p. on embryonic day 13; group III received paracetamol 100 mg/kg i.p. daily from embryonic day 13 to 21; group IV received paracetamol 300 mg/kg i.p. on embryonic day 13. Offspring were assessed for behavioral test parameters. Animal brains underwent histopathological and immunohistochemical analysis for brain-derived neurotrophic factor (BDNF). Offspring in groups II (valproic acid) and IV (single paracetamol dose) showed differences in neurobehavioral test parameters, supported by cerebellar and hippocampal pathology. BDNF-stained cerebellum and hippocampus sections from the valproic group and the single paracetamol group revealed focal staining in granular cerebellar cells and pyramidal hippocampal cells. These findings indicate that prenatal exposure to high doses of paracetamol induces neurodevelopmental pathology. The safety of paracetamol use during pregnancy requires further evaluation. Full article

Background: Acetaminophen (APAP) overdose remains a major cause of acute liver injury. Although N-acetylcysteine (NAC) is the clinically established antidote for APAP toxicity, its efficacy is greatest when administered early, and additional therapeutic strategies are still needed for patients with delayed presentation or progressive injury. Because APAP hepatotoxicity involves coupled disturbances in redox control, mitochondrial performance, and cellular metabolism, metabolic enzymes that sustain NADPH availability may critically influence disease severity. Malic enzyme 1 (ME1), a cytosolic NADPH-generating enzyme, has not been functionally defined in this context. Methods: To determine the contribution of ME1 to APAP-induced liver injury (AILI), we used hepatocyte-specific ME1 knockout mice, hepatic overexpression and reconstitution approaches, primary mouse hepatocytes, and an enzymatically inactive ME1 mutant. Liver injury and associated changes in oxidative stress, mitochondrial function, energy metabolism, autophagic flux, and endoplasmic reticulum (ER) stress were evaluated using biochemical, histological, molecular, and ultrastructural analyses, together with pharmacological interventions. Results: Genetic loss of ME1 did not substantially alter early APAP metabolic activation-related indices, including APAP-protein adduct formation, but markedly increased hepatocellular metabolic vulnerability after APAP challenge. This phenotype was characterized by enhanced lipid peroxidation, impaired mitochondrial polarization, reduced ATP availability, defective autophagic flux, and amplified ER stress, leading to more severe liver damage. In contrast, ME1 overexpression or reconstitution promoted a more adaptive metabolic response and limited tissue injury. These effects depended largely on ME1 catalytic activity, as protection was markedly weakened with the mutant enzyme. Pharmacological analyses further supported the involvement of AMPK/mTOR-associated autophagy regulation and ER stress adaptation in the downstream actions of ME1. Malic acid also partially attenuated APAP-induced hepatotoxicity in vivo and in vitro. Conclusions: ME1 functions as an endogenous metabolic factor that influences the outcome of APAP-induced liver injury. Its catalytic activity supports hepatocyte survival primarily by preserving reductive capacity, bioenergetic balance, and adaptive stress responses, rather than by altering APAP metabolic activation. Full article

Introduction: Uvular necrosis is a rare post-general anesthesia complication of airway instrumentation with an estimated 0.03% incidence characterized by delayed onset, disproportionate oropharyngeal pain, and uvular discoloration. Case Description: A 24-year-old male developed uvular necrosis following elective septoplasty–turbinoplasty under general anesthesia. Pain escalated 24–72 h post-operatively (8/10) and was refractory to oral analgesics (acetaminophen and tramadol). Topical 1% viscous lidocaine provided significant relief but required frequent application (q1–2 h). Pain decreased after day 6, with complete resolution by day 10. Conclusions: Uvular necrosis is an uncommon post-intubation complication. The take-home points of this study are as follows: (1) Uvular necrosis is characterized by delayed, disproportionate oropharyngeal pain and discoloration of the uvula. (2) Recommended treatments (oral analgesics, oral steroids, and topical lidocaine among others) are based on limited case reports. (3) Topical viscous lidocaine (1%) was an effective option in this case. Application with a cotton swab reduced dose and toxicity risk (20 to 2 mls) with no loss in analgesic efficacy. (4) Potential causes in this case include oral secretion suctioning, midline placement of endotracheal tube, and oropharyngeal manipulation. (5) Uvular necrosis is under-recognized and under-reported in anesthesia. Full article

Ferrate(VI) has increasingly been proposed as an environmentally friendly oxidant due to its high reactivity and the relatively low toxicity of its by-products. However, its performance in degrading emerging pollutants (EPs) has not been systematically compared with conventional systems. This study presents a novel comparative assessment of three oxidation systems for the degradation of acetaminophen (APAP): (i) Fe⁰-activated hydrogen peroxide (HP), (ii) Fe⁰-activated persulfate (PS), and (iii) a commercial ferrate(VI)-based product, Envifer^® (Fe(VI)). Optimal conditions were determined based on degradation kinetics, pH dependence, and oxidant stability. Oxidant systems were then evaluated in realistic matrices, including tap water and synthetic wastewater. When UP water was used, the HP/Fe⁰ system achieved the highest APAP mineralization (i.e., 66%) with 1 mM of oxidant dosage, and PS/Fe⁰ was shown to be effective without pH adjustment. Nevertheless, these heterogeneous systems presented serious limitations when applied in more complex matrices. Fe(VI) instead achieved a rapid APAP degradation even in the presence of carbonates and natural organic matter without pH adjustment. This represents a key advantage over HP- and PS-based systems, enabling simpler implementation and lower chemical demand. Furthermore, Fe(VI) resulted in lower dissolved iron concentrations, potentially enabling less intensive post-treatment requirements. Overall, the results identify Fe(VI)-based AOPs as a potentially green alternative to conventional systems for wastewater treatment. Full article

Liver regeneration after partial hepatectomy (PH) is critically influenced by redox balance, which may be severely disrupted under drug-induced liver injury. This study evaluated oxidative stress parameters and inflammatory markers in rats subjected to 70% PH following acetaminophen (APAP)-induced toxicity and assessed the preventive effect of the microalga Desmodesmus armatus. Reactive oxygen species (superoxide anion, hydroxyl radical, and hydrogen peroxide), antioxidant enzyme activities (superoxide dismutase and glutathione peroxidase), serum aminotransferases, bilirubin, and C-reactive protein were analyzed 0–168 h post-hepatectomy. APAP intoxication markedly increased mitochondrial ROS production, suppressed mitochondrial antioxidant enzyme activity, and prolonged elevations of ALT, AST, bilirubin, and CRP, accompanied by severe histological damage. Preventive administration of D. armatus suspension (10 mL/kg body weight at 1.5 × 10⁶ and 1.5 × 10⁷ cells/mL) attenuated oxidative stress in a dose-dependent manner. It significantly reduced ROS levels, restored mitochondrial antioxidant defenses, decreased cytolytic and cholestatic markers, and mitigated systemic inflammation. Overall, D. armatus exhibited hepatoprotective and redox-modulating properties, which may contribute to a more favorable microenvironment for liver recovery under toxic conditions. These findings highlight the potential of microalgae-based interventions as supportive strategies for reducing liver injury and improving recovery following acute liver injury. Full article

The management of patent ductus arteriosus (PDA) in premature infants remains a significant debate in neonatology. Interventions aimed at accelerating ductal closure, often using nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen, are common practice. However, recent evidence increasingly challenges this approach. Pharmacological agents for PDA closure demonstrate limited efficacy and carry significant risks of systemic toxicity, affecting renal, gastrointestinal, vascular, and pulmonary systems. Multiple recent randomized controlled trials (RCTs) and meta-analyses have largely failed to demonstrate that early active treatment improves crucial clinical outcomes such as mortality, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), or necrotizing enterocolitis (NEC). Some studies even suggest potential harm, particularly an increased risk of BPD and mortality in vulnerable extremely preterm infants. Procedural closure methods (surgical ligation, transcatheter techniques), while achieving anatomical closure, also pose significant risks and lack evidence of improved clinical outcomes. Given the high rates of spontaneous PDA closure, especially in extremely preterm infants, and the lack of proven benefit alongside potential harm from interventions, a paradigm shift towards expectant or conservative management is gaining support. This approach emphasizes supportive care, minimizing interventions, and may be complemented by the judicious use of postnatal corticosteroids in selected infants with significant lung disease, which might indirectly facilitate ductal closure by addressing underlying inflammation. Full article

Acetaminophen (APAP) overdose is a major global cause of drug-induced liver injury (DILI), and the rising incidence of APAP-induced hepatotoxicity has raised substantial concern in the medical community, highlighting an urgent need for effective therapeutic approaches. Coptidis Rhizoma alkaloids (CRAs) have shown hepatoprotective effects in multiple hepatic disease models. This study aimed to investigate the therapeutic efficacy and the underlying mechanisms of CRA in acetaminophen (APAP)-induced acute liver injury. After identifying 18 alkaloid components in CRA, we employed an integrated strategy of untargeted metabolomics and network pharmacological analysis to investigate the underlying mechanisms. The potential mechanisms were subsequently validated through histopathological examination and molecular biology assays. Our results showed that CRA exerted dose-dependent protection against APAP-induced liver injury in vitro and in vivo. This protective effect was mediated by enhanced hepatic glutathione (GSH) biosynthesis via increased intracellular cysteine (Cys) availability. In the mouse model, hepatic Cys and GSH levels were increased by 2.2-fold and 1.8-fold, respectively, relative to the model group, which consequently attenuated oxidative stress damage. Furthermore, CRA suppressed APAP-induced activation of ERK and NF-κB, reducing the phosphorylation levels by 39.2% and 38.0%, respectively. Accordingly, it also downregulated the subsequent expression of inflammatory mediators in the TNF signaling pathway. These findings provide crucial mechanistic insights into the hepatoprotective role of CRA against APAP-induced toxicity, establishing a valuable foundation for developing novel therapeutic or preventive strategies for APAP-induced liver injury. Full article

Precise control and measurement of the cellular microenvironment, particularly oxygen concentration, are crucial for developing physiologically relevant in vitro models. However, current methods often lack the spatial resolution and throughput needed to investigate complex, oxygen-dependent biological mechanisms in 3D cell cultures. Here, we present an advanced platform based on microcavity arrays featuring integrated, ratiometric oxygen sensors, so-called SensoSpheres. A unique bevel design at the cavity entrance enables the non-invasive, real-time measurement of pericellular oxygen concentration and oxygen gradients. We established protocols for generating spheroids from various cell lines (e.g., HepG2, HeLa) and characterized their metabolic responses under precisely controlled hypoxic, normoxic, and hyperoxic conditions. Using a dose–response assay, we demonstrate the platform’s sensitivity in capturing distinct metabolic shifts in response to acetaminophen and cisplatin. Furthermore, we introduce the Oxygen Consumption Recovery Rate (OCRR) as a novel parameter to quantify cellular resilience after exposure to toxic compounds such as cisplatin and acetaminophen. This high-throughput-compatible platform represents a significant methodological advancement, enabling detailed studies of oxygen-dependent cellular processes, drug toxicity, and metabolic adaptation. Its potential for integration into microfluidic systems paves the way for more sophisticated organ-on-chip models, ultimately improving the predictive power of preclinical research. Full article