Toxicology Research最新文献

Psoriasis is a chronic inflammatory skin disease with limited safe and effective treatments. Methylparaben, a widely used preservative in cosmetics, pharmaceuticals, and food, is an emerging environmental pollutant linked to immune-related skin disorders, but its role and mechanism in psoriasis remain unclear. This study explored its potential mechanism using network toxicology, molecular docking, molecular dynamics simulation, and eight machine learning algorithms. Methylparaben targets were retrieved from GeneCards and TCMSP, and psoriasis-related targets from CTD and GeneCards. Overlapping targets were screened with Venny 2.1.0. A PPI network was constructed via STRING, and core targets identified using Cytoscape 3.10.2. GO and KEGG enrichment analyses were performed on DAVID. Molecular docking evaluated the binding affinity of methylparaben with key targets. A total of 138 compound-related and 5,592 psoriasis-related targets were identified. Core targets such as INS, HIF1A, and PPARG are involved in regulating immune-inflammatory responses, keratinocyte proliferation and differentiation, and oxidative stress. GO analysis revealed enrichment in xenobiotic metabolism, lipopolysaccharide response, and metal ion binding. KEGG analysis highlighted pathways related to cancer, chemical carcinogenesis from reactive oxygen species, and drug metabolism via cytochrome P450 enzymes. Molecular docking showed stable binding of methylparaben to INS (-4.5 kcal/mol), HIF1A (-5.9 kcal/mol), and PPARG (-5.5 kcal/mol), primarily through hydrogen bonds and hydrophobic interactions. Methylparaben may exert its effects on psoriasis via multi-target and multi-pathway mechanisms, influencing inflammation, oxidative stress, and cellular regulation. These findings provide valuable insight into its toxicological mechanism and potential therapeutic application.

Bleomycin (BLM), a widely used chemotherapeutic agent, is associated with severe pulmonary toxicity, which can lead to irreversible pulmonary fibrosis (PF). The progressive nature of BLM-induced PF, coupled with the lack of effective preventive strategies, presents a major clinical challenge. Jiegan tea (JGT), a traditional herbal remedy derived from Platycodon grandiflorus (Jacq.) A. DC and Glycyrrhiza uralensis Fisch, has been proposed to offer protective effects against respiratory diseases. This study aims to evaluate the potential of JGT in mitigating BLM-induced pulmonary fibrosis and elucidate the underlying mechanisms. In vivo experiments demonstrate that JGT significantly reduces BLM-induced lung damage by inhibiting the epithelial-mesenchymal transition (EMT) pathway. Further mechanistic investigations reveal that JGT interacts with β-catenin, enhancing its stability, as confirmed by cellular thermal shift assays (CETSA). This stabilization of β-catenin prevents its nuclear translocation and subsequent accumulation, thereby suppressing the EMT process and mitigating fibrosis progression. These findings suggest that JGT holds promise as a natural preventive agent against BLM-induced pulmonary toxicity and fibrosis.

Prostate cancer (PC) is a common malignancy in men, and resistance to treatment in advanced stages remains a significant clinical problem. Docetaxel (DTX) is widely used in advanced PC therapy; however, its efficacy can be limited by toxicity and acquired resistance. Therefore, plant-derived compounds are being explored as supportive therapeutic agents. This study investigated the cytotoxic and antiproliferative effects of Thymus vulgaris (T. vulgaris) extract on PC-3 prostate cancer cells, both alone and in combination with DTX. PC-3 cells were treated with varying concentrations of T. vulgaris and DTX individually and in combination. Cell viability was measured using the MTT assay, and proliferative activity was assessed by AgNOR staining. Cell cycle distribution was analyzed using a Muse cell analyzer, apoptosis was detected via the TUNEL assay, and autophagy-associated protein expression (LC3 and p62) was examined immunohistochemically. T. vulgaris extract exhibited dose-dependent cytotoxicity with an IC⁵⁰ of 8 μg/mL. The combined treatment with T. vulgaris and DTX resulted in greater inhibition of cell viability, significant G0/G1 cell cycle arrest, increased apoptosis, and enhanced autophagy. Additionally, AgNOR analysis indicated reduced proliferative capacity. These findings suggest that T. vulgaris may enhance DTX efficacy and serve as a promising natural adjuvant in PC therapy.

Recent advancements in cancer immunotherapy have transformed clinical oncology, with monoclonal antibodies (mAbs), immune checkpoint inhibitors, adoptive cellular therapies, oncolytic viruses, cytokine based therapeutics and nanomedicine establishing themselves as core treatment platforms. Tumor heterogeneity driven by inter and intra tumoral genomic divergence generates complex neoantigen landscapes, contributing to immune evasion and therapeutic resistance. Natural antioxidants such as quercetin, curcumin, catechins and resveratrol are gaining recognition for their ability to modulate immunometabolic pathways by lowering pathological reactive oxygen species (ROS), restoring T-cell receptor signaling, enhancing dendritic antigen presentation and improving CD8⁺ T-cell infiltration, thereby strengthening foundational antitumor immune responses. Monoclonal antibodies generated from single B-cell clones demonstrate high antigen specificity and exert antitumor effects through antibody-dependent cellular cytotoxicity, complement activation and immune checkpoint modulation. Although checkpoint inhibitors achieve substantial clinical efficacy, they may induce severe immune-related adverse events, including myocarditis, colitis, and pneumonitis. Mechanistic studies further reveal that antioxidants such as EGCG, α-lipoic acid and curcumin downregulate PD-1/PD-L1 expression by restoring mitochondrial function and inhibiting STAT3 signalling, ultimately enhancing T-cell activation and reducing exhaustion, thereby improving responsiveness to checkpoint blockade. Adoptive cellular platforms, including CAR-T and CAR-NK therapies, offer durable clinical responses but face challenges such as cytokine release syndrome, antigen escape and neurotoxicity. AI-driven multi-omics analytics now achieve predictive accuracies enabling precision diagnostics, biomarker discovery and optimized treatment planning. Integrating Industry 6.0/7.0 technologies, intelligent manufacturing, sustainable materials, low-carbon bioprocessing, autonomous systems will facilitate globally accessible, highly targeted and toxicity-reduced immunotherapies, supporting equitable and environmentally responsible implementation of next-generation cancer treatments.

Anthracyclines, potent chemotherapeutic agents derived from Streptomyces species, play a pivotal role in the treatment of various malignancies, particularly haematologic and solid tumors in humans. Despite their efficacy, their clinical utility is hampered by dose-dependent, irreversible chronic cardiotoxicity, which contributes to rising morbidity and mortality among cancer survivors. This is a limitation and drawback of anthracycline drugs, which constrain their therapeutic potency, clinical effectiveness, pharmacological activity and therapeutic impact. Compromised pharmacodynamic efficacy compromises patient safety and poses significant obstacles to achieving remission, thereby affecting patient tolerability and increasing risk. Type-1 anthracycline-induced cardiotoxicity (AIC) involves progressive cardiomyocyte loss and heart failure, presenting a serious challenge in cardio-oncology. Recent advances have elucidated molecular mechanisms underpinning AIC, including topoisomerase II inhibition, oxidative stress (reactive oxygen species generation), and mitochondrial dysfunction, enabling targeted research and precision-based interventions. It elucidates advanced translational toxicology by enabling mitochondrial-targeted drug-induced cardiotoxicity, resulting in mitochondrial dysfunction offering precision-based cardiac function studies and optimising patient-specific clinical outcomes as study results. Using cardiac magnetic resonance and magnetic resonance spectroscopy (MRS) imaging techniques, the study further highlighted how advancements in emerging technology play a pivotal role in cardiac function studies. Over and above that, a detailed dissection with a thorough examination of the heart and its muscles through autopsy and histological analysis of cardiac tissue under the microscope revealed significant, substantial histopathological evidence, confirming the cardiotoxic effects. Anthracycline-associated cardiac complications with other agents encompass concerns such as: bradycardia, tachyarrhythmias, blocks in the heart's electrical signals, reduced blood flow to the heart muscle (myocardial ischaemia) and frequent hypotension.

Per- and polyfluoroalkyl substances (PFAS), such as PFHpA, PFOA, PFNA, and PFDA, are persistent environmental pollutants associated with multiple diseases. This study investigates the toxic mechanisms and pathways by which PFAS derivatives contribute to coronary artery disease (CAD) and renal arteriosclerosis. Using multiple databases, we identified toxic and disease-related targets and constructed a protein-protein interaction (PPI) network via the STRING database to analyze their interactions. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to identify relevant disease pathways. GO and KEGG results indicated significant enrichment in lipid metabolism, arteriosclerosis, cell proliferation, apoptosis, and inflammation. Molecular docking and dynamics simulations were used to evaluate the binding affinity and stability of PFAS derivatives with key targets. Core regulatory targets within the toxicity network-STAT3, MMP9, NFκB1, CASP3, AKT1, and PPARG-were found to mediate cardiotoxicity and nephrotoxicity through multiple pathways. Docking studies confirmed strong binding affinity (<-5 kcal/mol) between PFAS derivatives and these targets. Molecular dynamics simulations suggested that PFDA binds more stably to MMP9 than to other proteins. These findings indicate that PFAS derivatives may exacerbate renal and coronary arteriosclerosis by modulating lipid and arteriosclerosis signaling pathways and affecting key genes including STAT3, MMP9, and NFκB1. This study highlights potential mechanisms underlying PFAS-induced cardiovascular and renal damage.

Polygonum barbatum extract (PBE) is a traditional herbal remedy historically used for its analgesic, anti-inflammatory, and diuretic effects. However, its anticancer potential and underlying molecular mechanisms in colorectal cancer (CRC) remain largely unexplored. In this study, we demonstrate that PBE exerts potent cytotoxicity in CRC cells by inducing both the unfolded protein response (UPR) and autophagy. In vitro, PBE treatment resulted in a dose-dependent reduction of cell viability and colony formation in multiple CRC cell lines. Moreover, in a HCT116 xenograft mouse model, oral administration of PBE significantly inhibited tumor growth without inducing overt toxicity. Mechanistically, PBE increased the accumulation of acidic vesicular organelles and upregulated key UPR regulators-including BiP, IRE1, and PERK-accompanied by enhanced conversion of LC3-I to LC3-II and reduced p62 levels, indicative of elevated autophagic flux. Notably, co-treatment with chloroquine, an autophagy inhibitor, partially rescued cell viability, underscoring that autophagy contributes to PBE-induced cell death. In addition, PBE modulated several critical signaling pathways by inhibiting EGFR, mTOR, and STAT3 while concurrently activating downstream ERK and the AMPK-ACC axis. Collectively, these results reveal that PBE triggers ER stress-mediated UPR and autophagy to promote autophagic cell death in CRC, supporting its potential development as a novel therapeutic agent for colorectal cancer.

Radioresistance limits the efficacy of radiotherapy in non-small cell lung cancer (NSCLC). This study investigates whether carnosol, a natural diterpene from rosemary, enhances NSCLC radiosensitivity by modulating the miR-17-5p/TOLLIP/NF-κB axis. A549 cells were treated with carnosol (30 μM) and X-ray irradiation (6 Gy). Cell viability, apoptosis, and DNA damage were evaluated by CCK-8, clonogenic, TUNEL, and comet assays. qRT-PCR, Western blotting, and dual-luciferase assays assessed pathway components and interactions. Carnosol downregulated miR-17-5p and upregulated TOLLIP, suppressing TLR4 and p-NF-κB p65 while increasing IκBα expression. These alterations impaired DNA repair (evidenced by increased γH2AX and decreased RAD51), enhanced radiation-induced apoptosis, and reduced clonogenic survival (all P < 0.01). miR-17-5p mimics partially reversed these effects. Carnosol may exert its radiosensitizing effect in NSCLC by targeting the miR-17-5p/TOLLIP/NF-κB axis and disrupting DNA repair, highlighting its therapeutic potential in overcoming radioresistance.

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This study explores the risk of Torsades de Pointes (TdP) arrhythmia, focusing on the interactions of parent drugs and their metabolites with the Human ether-à-go-go-related gene (hERG) channel, which is crucial in cardiac electrical activity and TdP risk assessment. Using a dual-strategy molecular docking approach with AutoDock Vina and PatchDock, we analyzed clinically relevant ligand pairs: astemizole/desmethylastemizole, terfenadine/fexofenadine, and quetiapine/norquetiapine. Quantitative analysis revealed that high binding affinity does not always correlate with toxicity. For instance, the non-cardiotoxic metabolite fexofenadine exhibited a higher binding affinity (-9.3 kcal/mol) compared to its toxic parent terfenadine (-8.9 kcal/mol), but its safety is explained by physicochemical constraints (zwitterionic nature). Conversely, desmethylastemizole maintained high affinity (-9.2 kcal/mol) with a geometrically "relaxed" fit (Atomic Contact Energy: -338.36), rationalizing its sustained potency. Geometric analysis further distinguished quetiapine as a "steric blocker" (Contact Area: ~588 Å²) causing forced occlusion, whereas its metabolite norquetiapine acted as a specific ligand with a significantly smaller interface area (~417 Å²). These findings highlight the importance of focusing not only on the parent drug but also on metabolites for TdP risk assessment in new drug development. We advocate for an integrated computational framework combining binding energy, geometric complementarity, and physicochemical profiling to enhance the accuracy of early cardiac safety screenings.