Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: The transplacental transfer of xenobiotics, particularly in an enantioselective manner, is a critical and evolving area of developmental toxicology. Pregnant women, as a highly vulnerable population, are frequ... PubDate: 2025-06-07
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: Anthracycline anticancer agents, such as daunorubicin and doxorubicin, rank among the most effective and widely used anticancer drugs. However, their benefit is markedly reduced by the risk of severe cardiotox... PubDate: 2025-06-07
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: Cerium dioxide nanoparticles (CeO2 NP), or nanoceria, are versatile materials with interesting properties for industry and medicine fields, particularly redox properties and catalytic activity. Because of their d... PubDate: 2025-06-06
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: Angioplasties using drug-eluting stents remain the most common and effective intervention for coronary artery disease. However, in-stent restenosis (ISR) continues to be the leading cause of stent failure foll... PubDate: 2025-06-06
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: Organic solvents such as propylene glycol ethers (PGEs) represents more than 20 different substances and are incorporated in thousands of commercial and professional products. Two PGEs commonly used in Europe ... PubDate: 2025-06-05
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: Global manufacturing and utilization of medium-chain chlorinated paraffins (MCCPs) continue to rise due to the increasing regulation on short-chain chlorinated paraffins (SCCPs). Accumulating evidence reveals ... PubDate: 2025-06-05
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: Stony corals (Scleractinia) harbor abundant toxins as part of their survival strategy, and these molecules also provide novel lead candidates for drug development. In this study, we present the first comprehensive investigation of toxin profiles of the understudied Goniopora columna through transcriptome analysis, which has expanded the biochemical diversity of marine organism derived toxins. Then, a novel Kunitz-like polypeptide, named GcKuz1, which exhibits therapeutic potential for thrombosis was selected for functional studies and mechanistic investigation. In vitro experiments revealed that GcKuz1, at 2–16 μM, delayed plasma recalcification time and activated partial thromboplastin time without affecting prothrombin time. In murine models, GcKuz1, at 1–4 mg/kg dosage, significantly inhibited the FeCl3-induced carotid artery thrombosis and the carrageenan-induced mouse tail thrombosis. Moreover, GcKuz1 effectively attenuated thrombo-inflammation and cerebral tissue destruction, as well as restored blood–brain barrier integrity, in the transient middle cerebral artery occlusion model. Through enzyme kinetics assays and surface plasmon resonance (SPR) verification, GcKuz1 was shown to strongly inhibit the enzyme activity of plasma kallikrein (PKa) and FXIIa, two key factors involved in the contact-kinin pathway, via direct interaction, thereby exerting anticoagulation effects without impairing hemostasis. Notably, safety evaluation highlights the low toxicity, minimal hemolytic activity and reduced bleeding risk of GcKuz1, which underline its clinical availability. In conclusion, as a novel coral-derived protease inhibitor of FXIIa and PK, GcKuz1 offers potential therapeutic benefits in the treatment thrombosis-related cardiovascular diseases treatment by suppressing inflammation and preventing thrombus formation. PubDate: 2025-06-04
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: Drug-Induced Liver Injury (DILI) is a major challenge in drug development, occurring due to liver damage caused by the adverse effects of drugs or xenobiotics. High-throughput transcriptomics (HTTr) provides mechanistic insights into drug-induced hepatotoxicity, complementing traditional chemical structure-based methods. To address the challenges posed by DILI, this study aimed to evaluate the suitability of HTTr data for DILI classification and prediction. Initially, we reviewed the current landscape of HTTr-based DILI research, focusing on public datasets, computational tools, and bioinformatics techniques. Building on this foundation, we analyzed HTTr data from the Open TG-GATEs database, which includes primary human hepatocytes treated with 146 drugs at three concentrations. Gene expression data alone had limited ability to classify DILI phenotypes, performing similarly to chemical structure-based models. However, targeted gene sets improved clustering performance, and changes in clustering performance across concentration levels indicated that concentration information influences toxicity analysis. Machine learning models showed that integrating gene expression and chemical structure data enhanced predictive accuracy, emphasizing the need for multi-modal approaches. These findings underscore HTTr as a valuable tool for advancing DILI classification and prediction, contributing to more reliable drug safety assessments. PubDate: 2025-06-04
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: Micro- and nanoplastics (MPs/NPs), ubiquitous contaminants in ecosystems and food chains, have emerged as a significant concern due to their potential neurotoxic effects on human health. Here, we conducted a systematic review of the existing literature, which included 26 studies providing evidence from cellular and animal studies on the risks posed by MPs/NPs to the nervous system. In vitro studies reveal that MPs/NPs can disrupt the integrity of the blood–brain barrier, penetrate neurons and glial cells, impair cell membrane integrity, and induce cytotoxic effects. These plastic particles trigger oxidative stress, inflammation, and mitochondrial dysfunction, alter signaling pathways, and disrupt neuronal communication, potentially leading to neurological dysfunction, cognitive deficits, and neurodegenerative disorders like Alzheimer’s and Parkinson’s diseases. Animal models corroborate these findings, demonstrating behavioural changes, memory impairment and neurotransmitter imbalances following exposure to MPs/NPs. Although the evidence in humans is limited, the growing body of hazard data underlines the potential risks associated with chronic exposure and accumulation of MPs/NPs in the nervous system. This highlights the urgent need for further research to elucidate the mechanisms of neurotoxicity, as well as stringent regulatory measures to restrain plastic pollution and safeguard neurological health. PubDate: 2025-06-03
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: Several endogenous and exogenous mediators and pathogenic agents trigger inflammation. Despite the brain being less vulnerable to inflammation, many studies have underlined the contribution of inflammatory molecules in the pathogenesis of Parkinson’s disease (PD). The onset of the features of PD is the result of an interaction of multiple contributors. These factors include inflammatory mediators, α-synuclein accumulation, oxidative stress, mitochondrial dysfunction, and neuronal cell death. Due to multifaceted interaction and cross-talk amongst a bunch of proteins and pathways, deciphering the aetiology of PD has been quite complex and challenging. It is ambiguous whether inflammatory mediators lead to microglial activation and α-synuclein accumulation or vice versa. It is also unclear how inflammatory mediators cross the peripheral nervous system to the brain and trigger dopaminergic cell death. The present review provides an update on the involvement of inflammatory mediators and non-neuronal cells in dopaminergic cell death, which leads to sporadic PD in humans and PD-like features in rodents. The article emphasises the contribution of inflammatory molecules released from the peripheral nervous system in the selective, progressive, and slow demise of nigrostriatal dopaminergic neuronal cells of the midbrain. The article also narrates the challenges and future perspectives. PubDate: 2025-06-03
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: Aristolochic Acid (AA) is a class of naturally occurring compounds characterized by potent genotoxicity and carcinogenicity, predominantly found in plants of the Aristolochia genus. The 1993 Belgian weight-loss incident and subsequent research unequivocally established the association between AA and “Aristolochic Acid Nephropathy” (AAN) as well as Balkan Endemic Nephropathy (BEN), prompting global regulatory actions. AA undergoes nitroreduction to generate highly reactive intermediates, which form persistent DNA adducts, inducing A:T to T:A transversion mutations during DNA replication. In 2017, 78% (76/98) of hepatocellular carcinoma (HCC) samples collected from two Taiwanese hospitals exhibited the characteristic mutational signature COSMIC SBS22, sparking a global debate on whether AA contributes to liver carcinogenesis. This review systematically synthesizes the research progress on AA, encompassing its historical applications, metabolic mechanisms, genotoxic features, and its potential causal relationship with HCC. It highlights the necessity of employing multi-omics technologies to elucidate the regulatory networks of AA-metabolizing enzymes, developing non-invasive biomarkers, and rigorously validating carcinogenic mechanisms through animal models. Furthermore, strengthening the regulation of AA-containing herbal medicines and enhancing global exposure surveillance are imperative for mitigating the burden of liver cancer. This review provides a comprehensive perspective on the toxicological mechanisms and carcinogenic risks of AA, offering insights into precision prevention and intervention strategies. PubDate: 2025-05-30
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: F-53B, a substitute for perfluorooctane sulfonate (PFOS), has attracted considerable concerns due to its frequent detection in environment matrices. However, the potential health risks to mammals, especially neurodevelopmental toxicity, remain unclear. In this study, 3-week-old pubertal male rats were exposed to F-53B at concentrations of 0, 0.15, 1.5, and 15 μg/kg for 3 weeks continuously. Diminished cognitive abilities were observed by morris water maze (MWM) test, F-53B exposure increased the escape latency and decreased the time spent in the target quadrant of rats. Furthermore, F-53B significantly altered neurotransmitter levels in the hippocampus. Molecular docking studies indicated that F-53B might bind to metabotropic glutamate receptor 5 (mGluR5), potentially entering neurons and causing further neurotoxicity. qRT-PCR and western blot analyses were used to assess the expression of genes and proteins related to calcium pathways. Results revealed that F-53B exposure downregulated mRNA expression of ryanodine receptors (RyRs) and the phosphorylation of inositol trisphosphate receptors (IP3Rs), while upregulating sarco/endoplasmic reticulum Ca2+-ATPase2 (SERCA2) levels. F-53B inhibits the IP3/Ca2+ signaling pathway in the rat hippocampus, which may affect ER Ca2+ storage and release functions. Additionally, F-53B reduced the phosphorylation of IP3R, Ca2+/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinase 1 and 2 (ERK1/2), and cAMP response element binding protein (CREB), potentially impairing synaptic plasticity and long-term potentiation (LTP), leading to learning and memory deficits. This study reveals that F-53B induced neurodevelopmental toxicity linked to calcium pathway disruption and provides new insight into the potential long-term hazards of F-53B. PubDate: 2025-05-28
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: Over the last decade and worldwide, an enormous investment in research and data collection has been made in the hope of better understanding the possible ecological and toxicological impacts triggered by glyphosate (GLY). This broad-spectrum, systemic herbicide became the most heavily applied pesticide ever in the 2000s. It is sprayed in many different ways in both agricultural and non-agricultural settings, resulting in multiple routes of exposure to organisms up and down the tree of life. Yet, relatively little is known about the environmental fate of GLY-based herbicide (GBH) formulations, and even less on how GBH co-formulants alter the absorption, distribution, metabolism, excretion, and toxicity of GLY. The environmental fate of GLY depends on several abiotic and biotic factors. As a result of heavy annual GBH use over several decades, GLY residues are ubiquitous, and sometimes adversely affect non-target terrestrial and aquatic organisms. GLY has become a frequent contaminant in drinking water and food chains. Human exposures have been associated with numerous adverse health outcomes including carcinogenicity, metabolic syndrome, and reproductive and endocrine-system effects. Nonetheless, the existence and magnitude of GLY-induced effects on human health remain in dispute, especially in the case of heavily exposed applicators. A wide range of biochemical/physiological modes of action have been elucidated. Various GBH co-formulants have long been considered as inert ingredients relative to herbicidal activity but clearly contribute to GLY-induced hazards and risk gradients. In light of already-identified toxicological and ecosystem impacts, the intensive research focuses on GLY and GBHs should continue, coupled in the interim with commonsense, low-cost changes in use patterns and label requirements crafted to slow the spread of GLY-resistant weeds and reduce applicator and general-population exposures. PubDate: 2025-05-26
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: The increasing production and use of chemicals leads to a higher number of contaminants in (drinking) water sources, which poses significant challenges to those responsible for water quality. An important task for water companies and regulators is to ensure that (drinking) water quality does not compromise public health and confidence in water safety. A key component of this effort is toxicological risk assessment, which evaluates the safety of chemicals that may be present in water systems. Although there has been considerable progress in risk assessment methods, there is currently a lack of a clear approach to the risk assessment of chemicals in (drinking) water for which concentrations vary over time. In the current study, methods for the assessment of less than lifetime exposure (LTL) are presented that are particularly applicable for substances with time-varying concentrations in (drinking) water. The presented framework is a decision tree that helps experts to decide whether a measured or predicted LTL exposure to a chemical can lead to adverse health effects. To develop these methods, we used existing knowledge and incorporated new developments in toxicological risk assessment. A case study illustrates the application of the proposed approaches in a realistic scenario. The method can be used by risk assessors as a tool to improve the understanding of human exposure to contaminants in (drinking) water and to inform risk-based monitoring. In addition, it enables customised investigations and responses that lead to a more nuanced view of water quality and its impact on public health. PubDate: 2025-05-25
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: EPAA’s ‘NAM Designathon 2023’ challenge for human toxicity sought to identify a classification system capable of categorising chemicals based on their bioactivity and bioavailability properties determined using non-animal methodologies (Worth et al. 2025). The proposal is made to classify chemicals into three levels of concern: low concern could be used without restriction, medium concern requiring assessment to establish safe use levels and high concern being candidates requiring risk management (Berggren and Worth in Regul Toxicol Pharmacol 142:105431, https://doi.org/10.1016/j.yrtph.2023.105431, 2023). We developed a NAMs based classification system for “human systemic toxicity” mainly focussed on repeat dose toxicity, similar to the assessment carried out in classification for ‘Specific Target Organ Toxicity—Repeated Exposure’ (STOT-RE) based on ECETOC’s Tiered Approach integrating three lines of evidence: In silico predictions, In vitro bioavailability and PBK modelling, In vitro bioactivity assays. The first stage employed an in silico approach, covering several toxicity endpoints across various (Q)SAR in silico models to identify indicators of toxicity. Bioavailability was categorised by simulating 14-day plasma Cmax predictions for a standard dose level using three TK models (Firman et al. in Arch Toxicol 96:817–830, https://doi.org/10.1007/s00204-021-03205-x, 2022). Bioactivity was categorised using a matrix with potency and severity. In vitro data were obtained from ToxCast. Potency makes use of dose response AC50 values. Severity categorisation is based on consideration of the adverse effects associated with the assays. 12 chemicals have been assessed through the framework. Overall, we have demonstrated that the matrix suggested by the EPAA Designathon can be used to categorise chemicals into three different levels of concern but there are areas still to be explored especially for the range of assays used, the framework categorisation being defined, and how such a matrix would fit into a tiered approach, pragmatically, including targeted in vivo studies. PubDate: 2025-05-24
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: An emerging new trend reveals that potent synthetic cannabinoid receptor agonists (SCRAs) that were prevalent prior to the Chinese class-wide ban in July 2021 have remained on the market or re-emerged. This is likely because of a new production route where unscheduled tail-less precursors are converted into the desired controlled SCRA via a one-step synthesis. This study reports the discovery of a clandestine production site in Switzerland for this synthesis. Controlled recreations of the synthesis of ADB-BUTINACA (also known as ADB-BINACA or ADMB-BUTINACA) and MDMB-4en-PINACA based on a recipe recovered from the Swiss production site were undertaken. The recreations yielded oils or waxy products with chromatographic purities ranging from 39.3 to 93.4% with the precursors (ADB-INACA or MDMB-INACA) remaining in all products. Mixtures of a precursor (e.g., MDMB-INACA, ADB-INACA, AB-INACA, MDMB-ICA, ADB-IATA, MDMB-5’Me-INACA) with corresponding final SCRA(s) (e.g., MDMB-4en-PINACA, 4F-MDMB-BUTINACA, MDMB-BUTINACA, MDMB-FUBINACA, ADB-BUTINACA, ADB-4en-PINACA, AB-CHMINACA, 4F-MDMB-BUTICA, ADB-FUBIATA) were found in 28 forensic casework samples in the US received between February 2023 and February 2024 and 87 samples seized from the Scottish prisons between February 2023 and July 2024. In vitro CB1 receptor activity of the precursors, synthesized products, and mixtures of precursors and final SCRAs were examined using β-arrestin 2 recruitment and intracellular calcium release assays. The precursors were much less potent than the final SCRAs and the concentration of the final SCRA dictated the activity of mixtures. This study raises awareness of the emergence of a new production method for SCRAs as observed in multiple countries. PubDate: 2025-05-23
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: The range of e-cigarette flavors has driven consumer interest while raising concerns about potential health risks. However, the toxicological impact and chemical composition of flavored e-liquids remain poorly characterized. This study investigates cytotoxicity differences between tobacco- and non-tobacco-flavored e-liquids and identifies key compounds contributing to toxicity through chemical correlation analysis. We assessed the cytotoxicity of 100 e-liquids (50 tobacco-flavored, 50 non-tobacco-flavored) using IC50 values in NCI-H292 cells and selected representative samples for genotoxicity evaluation. Three component categories—principal constituents, organic acids, and cooling agents—were analyzed, alongside correlations between specific compounds and cytotoxicity. Our findings revealed that non-tobacco-flavored e-liquids exhibited significantly higher cytotoxicity than tobacco-flavored variants, with considerable variation across different flavors and nicotine concentrations. Among non-tobacco flavors, tropical fruit and melon varieties induced the greatest cytotoxicity. Genotoxicity analysis showed that while tobacco-flavored e-liquids (0.2 × to 1 × IC50) did not cause significant DNA damage, certain non-tobacco flavors (0.2 × to 1 × IC50) triggered pronounced DNA damage. Correlation analysis identified N,2,3-trimethyl-2-isopropylbutamide (WS-23), benzoic acid, and nicotine as negatively correlated with IC50 values, with WS-23 displaying the strongest association. Further in vitro validation confirmed that WS-23 (0–2.4 mg/mL) induces DNA damage and elevates reactive oxygen species (ROS) levels in a dose-dependent manner. These findings highlight the need for more rigorous investigation and regulatory oversight of flavored e-liquids to mitigate potential health risks. PubDate: 2025-05-22
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: The comprehensive in vitro proarrhythmia assay (CiPA) has paved the way for integrating in silico trials into drug evaluation processes. In alignment, the International Council for Harmonization (ICH) has initiated efforts to update the ICH S7B and E14 guidelines through a structured Questions and Answers (Q&A) format. A significant challenge in this paradigm is ensuring consistent application and evaluation of diverse proarrhythmia risk prediction models across experimental systems. This study utilized the CiPAORdv1.0 model to predict cardiac toxicity, leveraging in vitro data from 28 drugs for training and validation. A modified O'Hara–Rudy model simulated a virtual population of human ventricular cell models. Seven critical features (qNet, APD50, APD90, Camax, Carest, CaTD50, CaTD90) were extracted as inputs for analysis. CiPAORdv1.0 demonstrated robust performance, achieving predictive accuracies with an area under the curve (AUC) of 1.0 for high risk and 0.95 for low-risk categories. The calibration process was enhanced using normalized Euclidean distances (R1 and R2), effectively distinguishing risk categories. Sensitivity analysis identified key drugs, ensuring a strong calibration drug set to anchor model predictions. The proposed ANN model validated the CiPAORdv1.0 framework as an effective TdP-risk prediction system, ensuring robust and lab-specific validation. This study presents a novel algorithm leveraging artificial neural networks to implement validated cardiac safety models, addressing a critical need for standardized proarrhythmia risk assessment in drug development. PubDate: 2025-05-22
Please help us test our new pre-print finding feature by giving the pre-print link a rating. A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Abstract: The phenylpropene estragole (ES) is found in essential oils of herbs and spices, such as bitter fennel and basil. Humans are exposed to ES through the diet and phytomedicines. After its absorption, ES undergoes metabolic activation by CYP1A2 and SULT1A1 in the liver, which can give rise to DNA adducts and hepatocarcinogenesis. Until now, quantitative genotoxicity data for ES in human liver cells are scarce, correlating DNA adduct levels with critical effects such as clastogenicity. Here, we used human HepG2 and HepG2-CYP1A2 cells as well as primary human hepatocytes (PHH) to study the genotoxic, clastogenic and cytotoxic potential of ES and its crucial metabolite 1′-hydroxyestragole (1′OH-ES). In addition, primary rat hepatocytes (PRH) were used for selected endpoints. Treatment of HepG2-CYP1A2 cells with ES (0–2 mM) led to the concentration-dependent formation of E3′-N2-dG adducts. Apart from a moderate γH2AX induction, neither p53 accumulation nor cytotoxicity was observed. However, clastogenicity was demonstrated at ES concentrations ≥ 1 mM. Incubation of HepG2 cells with 1′OH-ES (0—35 µM) led to 10–50-fold higher E3′-N2-dG adduct levels compared to equimolar ES concentrations. Furthermore, 1′OH-ES caused γH2AX formation, p53 accumulation and cytotoxicity, which was confirmed in PHH. In agreement, 1′OH-ES induced clastogenicity at concentrations ≥ 25 µM. Molecular dosimetry revealed that a certain E3′-N2-dG adduct level is required to trigger clastogenicity and cytotoxicity. This was confirmed by Benchmark Concentration (BMC) modelling, showing that the BMC for clastogenicity is 12–17-fold higher than the respective BMC for DNA adduct formation. Our data indicate that a threshold level of DNA adducts is required, both in rat and human liver cells, to trigger markers of clastogenicity. These levels are unlikely to be reached in humans following chronic ES exposure through phytomedicines or the diet. PubDate: 2025-05-21
Hybrid journal (It can contain Open Access articles)
[2468 journals]
