Search Results (949)

Antipsychotic agents—spanning first-, second-, and third-generation drug classes—are emerging as mechanistically diverse candidates for repurposing in oncology. Although developed to modulate dopaminergic and serotonergic neurotransmission, some of these compounds exert pleiotropic effects on cancer cell survival, metabolism, and stemness. Across multiple malignancies, antipsychotics disrupt oncogenic signaling networks including PI3K/Akt/mTOR, STAT3/5, MAPK/ERK, and Wnt/β-Catenin, impair lysosomal and autophagic flux, and induce mitochondrial and calcium-dependent metabolic stress. Notably, several phenothiazines and dopamine-modulating agents selectively reduce cancer stem cell populations, suggesting potential utility in limiting recurrence and mitigating therapeutic resistance. These effects appear to involve disruption of CSC signaling pathways and interference with dopamine-dependent mechanisms that support stemness and survival. Preclinical studies consistently demonstrate antiproliferative, proapoptotic, antimetastatic, and chemosensitizing effects, whereas early clinical investigations demonstrate target engagement and feasibility but do not establish anticancer efficacy. Clinical trials of thioridazine in acute myeloid leukemia and chlorpromazine in glioblastoma show evidence of pharmacodynamic activity in patients, though these findings remain preliminary and non-efficacy-based. However, translation remains constrained by dose-limiting toxicities, pharmacokinetic barriers, and conflicting epidemiologic signals regarding long-term carcinogenic risk. Here, we synthesize mechanistic, translational, and emerging clinical findings relevant to antipsychotic repurposing in oncology, highlight tumor contexts in which these agents may hold potential, and outline future directions including biomarker-guided patient selection, rational combination strategies, and artificial intelligence (AI)-enabled drug-repurposing pipelines. Collectively, antipsychotics represent a promising yet underexplored class of multi-targeted agents; to define their full therapeutic potential will require rigorous mechanistic validation and carefully designed clinical trials. Full article

Highly aggressive gliomas remain difficult to treat because of their marked invasiveness, frequent recurrence, and association with glioma-related epilepsy. Increasing evidence suggests that ion channels expressed in glioma cells, including voltage-gated Na⁺ channels, large-conductance Ca²⁺-activated K⁺ (BK_Ca) channels, intermediate-conductance Ca²⁺-activated K⁺ (IK_Ca) channels, and inwardly rectifying K⁺ (Kir) channels, contribute to these malignant phenotypes and represent potential therapeutic targets. This perspective summarizes current evidence for eight representative drugs and phytoconstituents—perampanel, valproic acid, cilostazol, berberine, oxaliplatin, temozolomide, arecoline, and triptolide—that modulate these ion channels. Perampanel and valproic acid suppress voltage-gated Na⁺ current in glioma cells and may provide additional benefits in controlling glioma-associated epilepsy. Cilostazol activates BK_Ca channels, whereas berberine, oxaliplatin, and temozolomide inhibit IK_Ca channel activity. Arecoline suppresses IK_Ca and Kir channel activity, while triptolide inhibits Kir channels. These observations suggest that ion channel modulation may influence glioma cell proliferation, migration, invasion, and excitability. To complement the available experimental evidence, we performed molecular docking analyses as a hypothesis-generating approach to explore potential ligand–channel interactions. Because these computational predictions have not been experimentally validated, they should be interpreted cautiously and viewed as a framework for future mechanistic studies rather than definitive evidence of binding. We also discuss important translational considerations, including the limited clinical evidence and the toxicity profiles of several compounds. In particular, arecoline is associated with carcinogenicity and neurotoxicity, triptolide with significant systemic toxicity, berberine with poor oral bioavailability and potential drug interactions, and oxaliplatin with dose-limiting neurotoxicity. Overall, this perspective highlights ion channels as promising therapeutic targets in glioma while emphasizing the need for rigorous experimental validation and careful evaluation of safety before clinical translation. Full article

Formaldehyde is a chemical compound historically used for its antimicrobial and preservative properties. Due to its classification as a carcinogen and skin sensitizer, its use in cosmetics is restricted; however, formaldehyde-releasing preservatives are still permitted under specific conditions. The release of formaldehyde in cosmetic products may be influenced by factors such as temperature, storage time, and formulation matrix, raising potential safety and regulatory concerns. In this study, a full factorial design was applied to evaluate formaldehyde release in aqueous solutions at 40, 70, and 90 °C over 15, 30, and 60 min. In cosmetic matrices, temperatures of 40 and 70 °C were assessed at 0, 15, 30, and 60 min. Additionally, a three-month accelerated stability study was conducted to evaluate formaldehyde release over time in three different formulations. Formaldehyde release increased with both temperature and time in aqueous solutions, with diazolidinyl urea showing the highest levels, followed by DMDM hydantoin and imidazolidinyl urea. In cosmetic matrices, lower release levels were observed compared to aqueous systems; however, all formulations exceeded the 0.001% threshold established by European regulations. Under accelerated stability conditions, the emulsion exhibited the highest formaldehyde release, which may be associated with increased water availability promoting preservative hydrolysis. Overall, formaldehyde release was influenced by preservative structure, formulation matrix, temperature, and time. These findings highlight the importance of considering formulation composition and storage conditions in the evaluation of formaldehyde-releasing preservatives and may be relevant for safety assessment and regulatory compliance. Full article

Mycotoxin contamination in food and feed remains a major public health concern because of its potential toxicological impact and its global economic implications. Aflatoxins and ochratoxin A are of particular concern due to their carcinogenic, hepatotoxic, and nephrotoxic effects, highlighting the need for effective surveillance systems to reduce dietary exposure in the population. This study analyzes 2479 mycotoxin-related notifications concerning both food and feed reported through the iRASFF system during the period 2020–2024, with the aim of characterizing temporal notification trends, identifying the most affected food products and geographical regions, and evaluating the evolution of control strategies implemented by competent authorities. The results did not show a statistically significant long-term increasing trend in the number of mycotoxin notifications, although interannual fluctuations may reflect both changes in contamination patterns and improvements in detection and reporting systems. Products originating outside the European Union accounted for 90.44% of notifications and showed a significantly higher mean number of notifications than products originating within the European Union. Turkey (24%) and the United States (14%) were the most frequently reported countries of origin at a global level. Aflatoxins were the most frequently detected mycotoxins in food (84%), followed by ochratoxin A (15%), mainly affecting nuts, cereals, fruits, vegetables and herbs and spices. These findings demonstrate that mycotoxins continue to represent a persistent challenge for European food safety. Strengthening surveillance systems, enhancing international cooperation, and adapting control strategies to emerging environmental and trade-related factors are essential to minimize consumer exposure, particularly to compounds with genotoxic and carcinogenic potential, and to improve risk management within the food supply chain. Full article

Ethyl carbamate (EC) is a widely recognized carcinogen present in fermented foods, and enzymatic degradation is a safe and effective strategy for its reduction. An EC-degrading esterase derived from Acinetobacter calcoaceticus (AcECH) was previously identified. However, volatile ester compounds in Chinese Baijiu compete with EC for enzyme binding, thereby affecting degradation efficiency and flavor quality. In this study, molecular docking, molecular dynamics (MD) simulations, enzyme kinetics, bio-layer interferometry (BLI), and gas chromatography–ion mobility spectrometry (GC-IMS) were employed to investigate the substrate specificity of AcECH. Based on computational prediction and experimental validation, F157G has been identified as the most suitable mutant for improving substrate recognition. Compared with the wild-type enzyme, the degradation rates of ethyl acetate, ethyl valerate, and ethyl hexanoate decreased to 64.23%, 49.28%, and 34.08%, respectively. Meanwhile, F157G showed enhanced apparent binding affinity toward EC while largely maintaining EC hydrolytic activity, and reduced the degradation of desirable volatile esters, indicating an altered substrate preference of AcECH. Full article

Chiranthodendron pentadactylon Larreat (“flor de manita”) is traditionally used for gastrointestinal, cardiovascular, and neurological disorders. Objective: This study comprehensively integrated phytochemical characterization, in silico toxicological profiling, an exposure-informed Integrative Toxicity Prediction Model (ITPM), uncertainty analysis, and acute testing of a fresh flower aqueous extract (FFAE). Methods: Thirty-six phytochemicals were screened for hepatotoxicity, nephrotoxicity, Ames mutagenicity, carcinogenicity, hERG inhibition, reproductive-effects alerts, and acute oral toxicity. Five organ- or effect-specific endpoints were integrated into an exploratory Toxicological Alert Score (TAS), whereas reproductive alerts and predicted LD₅₀ were reported separately. Seventeen compounds quantified in the FFAE were compared with a 20-compound literature-informed profile through 50,000 Monte Carlo iterations. Male CD-1 mice received a single FFAE dose of 300–5000 mg/kg and were observed for 14 days. Results: Positive predictions occurred for hERG inhibition in 33 compounds (91.7%), hepatotoxicity in 29 (80.6%), nephrotoxicity and carcinogenicity in 28 each (77.8%), and mutagenicity in 21 (58.3%). Six compounds had predicted LD₅₀ values ≤ 1000 mg/kg. The proportional ITPM toxicity-evidence index was 6.91% for the experimental profile and 19.34% for the literature-informed profile. Monte Carlo means were 6.98% (95% uncertainty interval, 5.65–8.44%) and 19.32% (16.76–22.37%), respectively. No mortality, overt clinical signs, or treatment-related body weight differences occurred up to 5000 mg/kg. Conclusions: Compound-level predictions identified priorities for confirmatory testing, while the extract-specific model yielded a lower comparative toxicity-evidence proportion, and the animal study showed low overall acute toxicity under the evaluated conditions. These findings do not establish general or long-term safety, calibrated risk probabilities, or biological neutralization of toxicological liabilities. Full article

Accurately predicting the carcinogenicity of compounds is of great significance for drug discovery, clinical drug safety, and chemical risk assessment. Traditional methods for assessing carcinogenicity rely on animal testing, which suffers from limitations such as time-consuming processes, high costs, significant interspecies differences, and low predictive throughput. In recent years, computational modeling-based prediction methods (such as Quantitative Structure–Activity Relationships, QSAR) have made some progress, but they still face challenges such as insufficient molecular feature information and poor model interpretability. To overcome these barriers, the multimodal deep learning framework LMF-CP (Late Multimodal Fusion of Carcinogenicity Prediction) is proposed to enhance the performance and interpretability of compound carcinogenicity prediction. First, to comprehensively characterize the structural and physicochemical properties of compounds, a multimodal representation system based on four molecular modalities is constructed, namely SMILES sequences, molecular fingerprints, molecular images, and molecular graph structures. Specifically, Text Convolutional Neural Network (TextCNN), Multi-Layer Perceptron (MLP), Visual Geometry Group Network (VGGNet), as well as Molecular Graph Attention Network (MGAT) are employed to process this information, respectively. Second, to integrate information from different molecular representations, a late-stage fusion strategy based on Lasso stacking is employed. On the test set, LMF-CP achieves an area under curve (AUC) of 0.828, an accuracy (ACC) of 0.782, an F1 score of 0.786, a sensitivity (SEN) of 0.786, and a specificity (SPE) of 0.779. In addition, this paper combines Shapley Additive Explanations (SHAP) analysis with Bemis–Murcko scaffold analysis to interpret the model results from two perspectives. Finally, a visual online platform for predicting the carcinogenicity of compounds is designed, providing a convenient tool for the rapid assessment of compound carcinogenicity and structural interpretation. Full article

The widespread use of neonicotinoids (NEOs) poses a significant risk to school-aged children. However, critical knowledge gaps remain regarding their comprehensive exposure profiles and associated health risks. This study assessed the co-exposure levels and non-carcinogenic risks of 16 NEOs (including both traditional and emerging compounds) in 184 school-aged children recruited from a typical rural and urban area of South China. The sum concentrations of 16 NEOs (∑₁₆NEOs) ranged from 0.648 to 227 μg/L (median: 8.99 μg/L). The predominant compounds were clothianidin (CLO, 1.93 μg/L), N-desmethyl-acetamiprid (N-dm-ACE, 1.64 μg/L), thiamethoxam (THM, 0.792 μg/L), and dinotefuran (DIN, 0.222 μg/L). To our knowledge, this is the first report of emerging NEOs—paichongding (IPP), sulfoxaflor (SUL), and flonicamid (FLO)—in children urine, with detection frequencies of 11.4%, 68.2%, and 53.4%, respectively. Significant rural–urban disparities in urinary concentrations were observed. The metabolite-to-parent ratios (e.g., N-dm-ACE/ACE, 5-OH-IMI/IMI, and THCP-AM/THCP) may serve as a useful biomarker for assessing human exposure to NEOs, as it provides valuable insight into the metabolic fate of the target compounds and aids in distinguishing exposure pathways. The median estimated daily intake (EDI) values for CLO, N-dm-ACE, THM, and ∑₁₂NEOs were 0.127, 0.117, 0.046, and 0.696 μg/kg-bw/day, respectively. Although the hazard quotient for individual compounds was below 1 for vast majority of school-aged children, cumulative exposure assessment indicated that 1.09% of participants had a hazard quotient exceeding 1 for both IMI_eq and ∑₁₂NEOs, suggesting potential health concerns under co-exposure scenarios. Using a multi-criteria Toxicological Priority Index (ToxPi) model, CLO, THM, thiacloprid-amid (THCP-AM), and N-dm-ACE were identified as the high-priority compounds requiring regulatory attention in children’s environmental health. This study provides the first comprehensive biomonitoring and ToxPi-based prioritization of both traditional and emerging NEOs in school-aged children in South China. The findings highlight the urgent need for continued monitoring, refined mixture risk assessment, and regulatory consideration of emerging substitutes and their metabolites, which are not adequately covered by current safety guidelines. Full article

To reveal the chemical composition and concentration distribution, spatial distribution characteristics, source composition, and health impacts of volatile organic compounds (VOCs) in the two multi-industry industrial parks in Tianjin, 57 VOC species were determined by using SUMMA canister sampling with preconcentration gas chromatography/mass spectrometry. Based on these measurements, the Positive Matrix Factorization (PMF) model was used for source analysis to achieve quantitative identification and contribution analysis of different source factors. The health risks of VOC concentrations were analyzed based on the assessment framework recommended by the United States Environmental Protection Agency (USEPA). The results showed that the average concentrations of TVOCs in A-1 (Industrial Park and Cluster A, 5 m), A-2 (Industrial Park and Cluster A, 10 m), B-1 (Industrial Park and Cluster B, 5 m), and B-2 (Industrial Park and Cluster B, 10 m) were 59.72 ppbv, 45.35 ppbv, 32.44 ppbv, and 21.65 ppbv, respectively. TVOC concentrations were higher at A-1 and B-1 than at A-2 and B-2, and were generally higher at site A than at site B. The VOC components were mainly alkanes (53.5%–71.4%), followed by aromatic hydrocarbons (15.6%–36.2%), alkenes (4.6%–9.9%), and alkynes (3.1%–7.6%). The proportion of aromatic hydrocarbons in A was higher (22.13% and 36.22%), while alkanes dominated absolutely in B (71.4% and 66.9%). n-Hexane was the key species driving the spatial differences (a typical source of VOCs in solvent usage). The concentration in A-1 was 3.1 times that of A-2, and B-1 was 3.3 times that of B-2. It was mainly controlled by local solvent unorganized emissions. The differences in species between the two points at site A for toluene, xylene, etc., were relatively gentle, while at site B, the concentration of the same aromatic hydrocarbons at B-1 was significantly higher than that at B-2, presenting a clearer spatial characteristic, indicating differences in the spatial distribution of organic solvent-related industrial activities in different sites. The source analysis showed that A-1 was dominated by solvent usage (38.64%) and natural gas/LPG sources (36.96%); A-2 by vehicle exhaust (40.20%) and natural gas/LPG sources (36.15%); B-1 by cleaning-agent usage (38.81%) and fuel combustion (30.33%); and B-2 by plastic and rubber production (36.90%) and fuel combustion (31.84%). The health risk assessment showed that benzene, n-hexane, and xylene dominated the non-carcinogenic risks, but the overall non-carcinogenic (HI < 1) and carcinogenic (CR < 1 × 10⁻⁶) risks were both below the threshold. This study reveals inter-site differences in VOC concentrations, compositions, and source contributions across two mixed industrial parks, providing a basis for site-specific VOC control priorities, source-targeted monitoring strategies, and risk management in mixed industrial areas. Full article

In recent years, increasing attention has been paid to limiting the use of nitrates and nitrites in meat products due to concerns regarding their potential health implications. Despite their important technological role in ensuring microbiological safety, oxidative stability, and the development of sensory characteristics of meat products, their use raises health concerns among consumers. These concerns are primarily associated with the potential formation of N-nitrosamines, some of which have been classified possible human carcinogens. In this context, there is growing interest in natural functional additives consistent with the clean-label concept and the zero-waste approach, including raw materials derived from fruit-processing by-products. Fruit-processing by-products, especially berry pomace, are a rich source of phenolic compounds with antioxidant and antimicrobial properties. Current evidence indicates that the bioactive compounds present in berry pomaces effectively reduce lipid oxidation and exhibit antimicrobial potential, which may contribute to inhibiting the growth of undesirable microorganisms in meat products. However, the effectiveness of this activity depends on several factors, including the type of berry pomace, its phenolic profile, the form of application (e.g., powder, extract, or freeze-dried material), the concentration applied, the type of meat product and the storage conditions. Consequently, berry pomaces should be regarded as natural ingredients supporting nitrite reduction strategies in meat products rather than as complete substitutes for nitrites. Furthermore, although berry pomaces exhibit considerable functional potential, their effectiveness in reducing nitrite levels depends on the type of meat product, its formulation, and the applied processing conditions. Among berry pomaces, red currant pomace (Ribes rubrum) has recently attracted increasing scientific interest because of its rich phenolic profile and promising functional properties. However, compared with chokeberry, blueberry, blackberry, and blackcurrant pomaces, relatively few studies have investigated its application in meat products. Therefore, further research is needed to confirm its technological functionality, antimicrobial efficacy, and potential contribution to nitrite-reduction strategies under different meat-processing conditions. Full article

Lung cancer mortality is a critical issue in Northern Thailand, where incidence rates significantly exceed the national average. Key risk factors include tobacco smoking and seasonal air pollution from biomass burning, which releases carcinogenic polycyclic aromatic hydrocarbons (PAHs). This study aims to analyze the accumulation of 16 priority PAHs in human lung tissues to explore links between environmental exposure, smoking habits, and cancer development. Tissue samples (normal, para-cancerous, and adenocarcinoma) were collected from 30 surgical participants (15 lung cancer patients, 15 non-cancer controls) at Chiang Mai University Hospital. Compounds were extracted via ultrasonication and quantified using gas chromatography-mass spectrometry. Carcinogenic potency was evaluated using Benzo[a]pyrene equivalents, with concentrations compared across tissue types and patient groups using generalized estimating equations. High-molecular-weight PAHs were the dominant species, accounting for over 50% of total accumulation in all tissues, aligning with regional biomass burning profiles. Total concentrations and carcinogenic potency were significantly higher in smokers, particularly within normal lung tissues. Furthermore, high-molecular-weight PAH concentrations positively correlated with tissue cholesterol levels (R = 0.66). Source analysis indicated exposure primarily from pyrogenic sources, alongside petroleum emissions. In conclusion, high-molecular-weight carcinogens significantly accumulate in human lungs in Northern Thailand, reflecting substantial environmental exposure, while tissue lipid content modulates toxin bioaccumulation. Smoking facilitates compound retention in normal tissues, underscoring an urgent need for targeted public health strategies addressing both environmental pollution and tobacco use. Full article

The LW-9 peptide was previously identified through screening of purified molecules from the venom of the spider Phoneutria nigriventer and has been described as an immunomodulatory compound with potential application in cancer therapy. The molecule was biochemically characterized and subjected to in silico analyses to evaluate its toxicity and efficacy profiles. LW-9 exhibits a molecular mass of 1235.522 Da and the amino acid sequence PyrKKDRFLGLM-CONH₂. Secondary and tertiary structures were modeled using computational approaches. The results indicated low permeability across biological membranes, including the blood–brain barrier. In silico predictions further suggested that LW-9 is neither carcinogenic nor mutagenic; however, it may act as a potent inhibitor of the CYP3A4 enzyme, raising concerns regarding potential drug–drug interactions. Overall, LW-9 shows promise as an immunomodulatory agent for cancer applications, while its pharmacokinetic properties and possible interactions with other drugs continue to be investigated. Full article

The Assaluyeh coastal industrial zone, home to extensive oil, gas, and petrochemical facilities, is among Iran’s most environmentally stressed regions. Despite numerous project-specific Environmental Impact Assessments (EIAs), environmental degradation persists, revealing systemic gaps in the conventional EIA framework. This study reviews publicly available EIA and Environmental, Social, and Health Impact Assessment (ESHIA) reports, alongside scientific literature from 2015 to 2024, to assess whether cumulative impacts have been adequately considered. Analysis focused on the explicit mention of cumulative effects, methodological rigor, and transparency of documentation. Findings indicate that most EIAs overlook cumulative impacts, focusing primarily only on individual project boundaries. Field-based studies further confirm significant accumulation of heavy metals (Pb, Cd, Ni, V), polycyclic aromatic hydrocarbons (PAHs), BTEX compounds, and particulate matter, reflecting the cumulative influence of multiple pollution sources and synergistic interactions. Key quantitative findings include: heavy metal concentrations in the central industrial zone reaching Pb = 120 µg/g and Ni = 45 µg/g with PLI = 2.5; organic pollutant levels of ΣPAH = 72.5 µg/m³ and BTEX = 38.2 µg/m³, both exceeding the WHO guideline of 20 µg/m³; carcinogenic risk classified as High for Cd and Hg (exceeding EPA acceptable limits); and strong pollutant correlations (PAH–BTEX: r = 0.80). These results underscore the urgent need for the implementation of a regional Cumulative Effects Assessment (CEA) integrated within a Strategic Environmental Assessment (SEA) framework, which can improve environmental governance and promote long-term sustainability in Iran’s industrial coastal zones. Full article

The dramatic rise in global aquaculture has brought renewed focus on filamentous fungi impacting fish health and aquafeeds. The fungal genus Aspergillus has a Janus-like role in aquaculture. On the pathogenic side, opportunistic pathogens like A. flavus, A. niger and A. fumigatus cause outbreaks of aspergillosis, with granulomatous lesions and significant mortality, especially in fish with impaired immunity and/or poor environmental conditions. Toxigenic strains of A. flavus and A. parasiticus also contaminate aquafeeds with aflatoxins, some of the most toxic natural hepatotoxins and carcinogens, which have been shown to affect growth, immunity and aflatoxin residues in edible fish fillets. On the positive side, non-toxigenic strains of A. niger, A. oryzae and A. awamori are increasingly used as fungal probiotics, solid-state fermenters to upgrade plant protein feed supplements, and as sources of industrially useful hydrolytic enzymes, secondary metabolites and antifungal compounds. Synthesizing evidence from over 90 peer-reviewed studies, this narrative review elucidates how species, strain, and rearing context jointly determine whether Aspergillus behaves as a pathogen or as a functional additive. We highlight knowledge gaps, offer an interpretative model and suggest practical strategies to limit risks and leverage the biotechnological uses of Aspergillus for sustainable aquaculture. The novelty of this review lies in integrating, within a single finfish-focused framework, the three usually separate faces of Aspergillus—pathogen, aflatoxin producer, and functional feed additive—and in translating this dual nature into practical, strain-level guidance for aquaculture. Full article

Volatile organic compounds (VOCs) are the main precursors of ozone (O₃) and secondary organic aerosols (SOAs), posing a significant threat to the environment and human health. In this study, the characteristics, potential for the generation of O₃ and SOAs, sources and health risks of volatile organic compounds were investigated based on annual monitoring data for 2021 in Dezhou, which is located in the northwest of Shandong Province, China, and adjacent to the Beijing–Tianjin–Hebei region. The results showed that the ambient VOC concentrations were lower in spring and summer and higher in autumn and winter. The species contributing to the O₃ formation potential (OFP) and SOA formation potential (SOAFP) varied by season, but those with high contributions were all olefins and aromatic hydrocarbons. O₃ pollution occurred frequently in summer, with a proportion of 40.22%. Focusing on summer, six sources were identified through the positive matrix factorization (PMF) model, with the petrochemical industry (26.1%) and combustion (25.6%) being the primary sources. The non-carcinogenic risk values of the involved 18 toxic VOCs were all within the safety threshold, while the carcinogenic risk of benzene was regarded as low-probability under long-term exposure. This study provides significant support for targeted control of air pollutant emissions and improvement in regional air quality. Full article