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Results for “pharmacology and toxicology”

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bioRxiv2021

Preclinical and Toxicology Studies of BRD5529, a Selective Inhibitor of CARD9

BackgroundExuberant inflammation during Pneumocystis pneumonia leads to lung injury. CARD9 is a central mediator of inflammatory signaling mediated by C-type lectin receptors. CARD9 inhibitor BRD5529 has been shown to be an effective in vitro inhibitor of Pneumocystis {beta}-glucan-induced proinflammatory signaling and downstream TNF-alpha production, suggesting its viability as a candidate for preliminary drug testing as an anti- inflammatory agent in the rodent Pneumocystis pneumonia model (PCP). MethodsTo assess for potential toxicity, mice were injected intraperitoneally (IP) daily either with vehicle or BRD5529 at 0.1 mg/kg or 1.0 mg/kg for two weeks. Mouse weights were taken daily. At day 14, mice were euthanized, weighed, and analyzed by flexiVent for lung stiffness. Lungs, liver, and kidney were then harvested for H&E staining and pathology scoring. Lung samples were further analyzed for proinflammatory cytokines via ELISA and extracellular matrix generation via quantitative PCR (q-PCR). Blood collection postmortem was performed for blood chemistry analysis. ResultsBRD5529 at both doses of IP administration resulted in no significant changes in daily or final weight gain. Analysis of lung stiffness by flexiVent showed no significant differences between the control or treated groups. Furthermore, ELISA results for proinflammatory IL-1 Beta, IL-6, and TNF-alpha showed no major differences in the respective groups. qPCR analysis of extracellular matrix transcripts collagen type I, alpha 1 (Col1a1) and fibronectin (Fn) were statically similar as well in the treated and control groups. Examination and pathology scoring of H&E slides from lung, liver, and kidney from the each of the mice in all groups and subsequent pathology scoring showed no significant change. Blood chemistry analysis revealed similar, non-significant patterns. ConclusionsBRD5529 in our initial general safety and toxicology assessments displayed no inherent safety concerns in the analyzed parameters. These data support broader in vivo testing of the inhibitor as a timed adjunct therapy to the deleterious proinflammatory host immune response often associated with anti-Pneumocystis therapy.

pharmacology and toxicology↗

bioRxiv2024

Title: 4-week GLP immunotoxicity assessment of lactoferrin alpha produced by Komagataella phaffii in Sprague Dawley rats

Oral toxicity and toxicokinetic properties of human lactoferrin (LF) alpha produced in Komagataella Phaffii (effera) were investigated in adult Sprague-Dawley rats over a 28-day period under good laboratory practice conditions. Main study dosing used groups of 10 rats/sex/dose, and a secondary study evaluating toxicokinetic parameters used 6 rats/sex/dose. The vehicle control group received sodium citrate buffer, test groups received daily doses of 200, 600, and 2000 mg of effera per kg body weight, and the comparative control group received 2000 mg bovine LF (bLF)/kg body weight per day. T-cell dependent antibody response against keyhole limpet hemocyanin and immunophenotyping of the spleen were performed as measures of immunotoxicity. Clinical observations, body weight, hematology, coagulation, clinical chemistry, urinalysis, immunotoxicity, gross necropsy, and histopathology were assessed. Toxicokinetic parameters were analyzed as an indication of LF bioavailability, and anti-LF antibody assays were conducted to detect antibodies produced against LF to measure immunogenicity. No treatment related toxicologically significant changes were observed. Based on the absence of toxicologically relevant changes, effera is well tolerated in rats at doses up to 2000 mg rhLF/kg/day, an amount [~]400 times that of the estimated daily intake at the 90th percentile proposed for human adult use.

pharmacology and toxicology↗

bioRxiv2023

Targeting staphylococcal cell-wall biosynthesis protein FemX through steered molecular dynamics and drug-repurposing approach

Staphylococcus aureus-mediated infection is a serious threat in this antimicrobial-resistant world. S. aureus has become a superbug by challenging conventional as well as modern treatment strategies. Nowadays, drug repurposing has become a new trend for the discovery of new drug molecules. This study focuses on evaluating FDA-approved drugs that can be repurposed against S. aureus infection. Steered molecular dynamics (SMD) has been performed for Lumacaftor and Olaparib against staphylococcal FemX to understand their binding to the active site. A time-dependent external force or rupture has been applied to the ligands to calculate the force required to dislocate the ligand from the binding pocket. SMD analysis indicates that Lumacaftor has a high affinity for the substrate binding pocket in comparison to Olaparib. Umbrella sampling exhibits that Lumacaftor possesses a higher free energy barrier to displace it from the ligand-binding site. The bactericidal activity of Lumacaftor and Olaparib has been tested, and it shows that Lumacaftor has shown moderate activity along with biofilm inhibition potential (MIC value with conc. 128 g/mL). Pharmacokinetic and toxicology evaluations indicate that Lumacaftor has higher pharmacokinetic potential with lower toxicity. This is the first experimental report where staphylococcal FemX has been targeted for the discovery of new drugs. It is suggested that Lumacaftor may be a potential lead molecule against S. aureus.

pharmacology and toxicology↗

bioRxiv2024

Toxicogenomic Assessment of In Vitro Macrophages Exposed to Profibrotic Challenge.

Immune signalling is a crucial component in the progression of fibrosis. However, approaches for the safety assessment of potentially profibrotic substances, providing information on mechanistic immune responses, are underdeveloped. This study utilises a comprehensive analysis of RNA sequencing data from macrophages exposed in vitro to multiple sublethal concentrations of the profibrotic agent bleomycin, over multiple timepoints. Using a toxicogenomic framework, we performed dose-dependent analysis to filter genes truly altered by bleomycin exposure from noise and identified a subset of immune genes with a sustained dose-dependent and differential expression response to profibrotic challenge. We performed an immunoassay and revealed cytokines and proteinases responding to bleomycin exposure that closely correlate to transcriptomic alterations, underscoring the integration between transcriptional immune response and external immune signalling activity. This study not only increases our understanding of the immunological mechanisms of fibrosis, but also offers an innovative framework for the toxicological evaluation of substances with potential fibrogenic effects on macrophage signalling. Our work brings a new immunotoxicogenomic direction for hazard assessment of fibrotic compounds, through implementation of a time and resource efficient in vitro methodology.

pharmacology and toxicology↗

bioRxiv2024

Efficacy and safety of an mRNA-based RSV preF vaccine in preclinical studies

The transmembrane fusion (F) protein of RSV plays important roles in RSV pathogenesis as it mediates the fusion between virus and the target cell membrane. During the fusion process, F protein transits from a metastable state (prefusion, preF) to a stable state after merging of virus and cell membranes (postfusion, postF). The majority of highly neutralizing antibodies induced by natural infection or immunization targets the preF form, making it the preferred antigen for vaccine development. Here, we evaluate the mRNA vaccine candidate, STR-V003, which encapsulates the modified mRNA encoding the preF protein in lipid nanoparticles (LNPs). This vaccine demonstrated robust immunogenic in both mice and cotton rats. STR-V003 induced high levels of neutralizing antibodies and RSV preF-specific IgG antibodies, and significantly reduced the RSV viral loads in the lung and nose tissue of challenged animals. In addition, STR-V003 did not have obvious enhancement of lung pathology without causing vaccine enhanced disease (VED). The repeated dose general toxicology studies and local tolerance studies of STR-V003 were evaluated in rats. Therefore, STR-V003 has an acceptable safety profile and robust protective immunity against RSV, and has been approved by the FDA to enter phase I clinical study (NCT06344975).

pharmacology and toxicology↗

bioRxiv2019

Development of a hybrid Bayesian network model for predicting acute fish toxicity using multiple lines of evidence

A Bayesian network was developed for predicting the acute toxicity intervals of chemical substances to fish, based on information on fish embryo toxicity (FET) in combination with other information. This model can support the use of FET data in a Weight-of-Evidence (WOE) approach for replacing the use of juvenile fish. The BN predicted correct toxicity intervals for 69%-80% of the tested substances. The model was most sensitive to components quantified by toxicity data, and least sensitive to components quantified by expert knowledge. The model is publicly available through a web interface. Further development of this model should include additional lines of evidence, refinement of the discretisation, and training with a larger dataset for weighting of the lines of evidence. A refined version of this model can be a useful tool for predicting acute fish toxicity, and a contribution to more quantitative WOE approaches for ecotoxicology and environmental assessment more generally.\n\nHighlightsO_LIA Bayesian network (BN) was developed to predict the toxicity of chemicals to fish\nC_LIO_LIThe BN uses fish embryo toxicity data in a quantitative weight-of-evidence approach\nC_LIO_LIThe BN integrates physical, chemical and toxicological properties of chemicals\nC_LIO_LICorrect toxicity intervals were predicted for 69-80% of test cases\nC_LIO_LIThe BN is publicly available for demonstration and testing through a web interface\nC_LI

pharmacology and toxicology↗

bioRxiv2021

Quantifying and Mitigating Motor Phenotypes Induced by Antisense Oligonucleotides in the Central Nervous System

Antisense oligonucleotides (ASOs) are emerging as a promising class of therapeutics for neurological diseases. When injected directly into the cerebrospinal fluid, ASOs distribute broadly across brain regions and exert long-lasting therapeutic effects. However, many phosphorothioate (PS)-modified gapmer ASOs show transient motor phenotypes when injected into the cerebrospinal fluid, ranging from reduced motor activity to ataxia or acute seizure-like phenotypes. The effect of sugar and phosphate modifications on these phenotypes has not previously been systematically studied. Using a behavioral scoring assay customized to reflect the timing and nature of these effects, we show that both sugar and phosphate modifications influence acute motor phenotypes. Among sugar analogues, PS-DNA induces the strongest motor phenotype while 2-substituted RNA modifications improve the tolerability of PS-ASOs. This helps explain why gapmer ASOs have been more challenging to develop clinically relative to steric blocker ASOs, which have a reduced tendency to induce these effects. Reducing the PS content of gapmer ASOs, which contain a stretch of PS-DNA, improves their toxicity profile, but in some cases also reduces their efficacy or duration of effect. Reducing PS content improved the acute tolerability of ASOs in both mice and sheep. We show that this acute toxicity is not mediated by the major nucleic acid sensing innate immune pathways. Formulating ASOs with calcium ions before injecting into the CNS further improved their tolerability, but through a mechanism at least partially distinct from the reduction of PS content. Overall, our work identifies and quantifies an understudied aspect of oligonucleotide toxicology in the CNS, explores its mechanism, and presents platform-level medicinal chemistry approaches that improve tolerability of this class of compounds.

pharmacology and toxicology↗

bioRxiv2022

Flavor Classification/Categorization and Differential Toxicity of Oral Nicotine Pouches (ONPs) in Lung Epithelial Cells

The prevalence of flavored tobacco product usage amongst youth in the United States is partly due to the emergence of non-combustible nicotine-containing products (NCNPs), including oral nicotine pouches (ONPs) and smokeless tobacco products. ONPs are available in various different flavors (mint, fruity, tobacco, dessert, citrus, coffee, wintergreen, and berry) and may use either Tobacco-Derived Nicotine (TDN) or Tobacco-Free Nicotine (TFN). Currently, several brands of ONPs are sold in the U.S and comprise a significant portion of NCNP sales in the U.S. There is a growing concern that flavored ONPs may not only induce oral health effects, but may also induce systemic toxic effects due to nicotine and other ONP byproducts being absorbed into systemic circulation through the oral mucosa. These byproducts can act locally on other tissues and may potentially cause redox dysregulation and heightened inflammatory responses systemically in the respiratory, cardiovascular, and/or renal systems. Hence, we determined the effects of flavored ONPs from four of the most widely sold brands in the U.S in inducing toxicological effects on the respiratory epithelium. Prior to analyzing the effects ONPs, we first classified ONPs sold in the US based on their flavor and the flavor category to which they belong to using a wheel diagram. Subsequently, using human bronchial epithelial cells (16-HBE and BEAS-2B) exposed to extracts of flavored ONPs, we assessed the levels of ONP-induced inflammatory cytokine release (IL-6 and IL-8), cellular Reactive Oxygen Species (ROS) production, and cytotoxicity in the airway epithelium. Our data showed that cells exposed to the lowest concentration treatments showed increased cytotoxicity, differential cellular ROS production, and proinflammatory cytokine release. The most striking response was observed among cells treated with the spearmint ONP, whereas ONPs containing original tobacco and fruity flavors showed varied levels of ROS release in 16-HBE cells. Our data suggest that flavored ONPs are unsafe and likely to cause systemic and local toxicological responses during chronic usage. Our study is a part of ongoing efforts to use in vitro, ex-vivo, and in vivo systems to understand how the usage of various flavored ONPs may cause both oral and pulmonary toxicity, and impact human periodontal health.

pharmacology and toxicology↗

bioRxiv2025

Accelerated plastic aging in suspension (APAS): A simple, reproducible approach for the generation of model micro- and nanoplastics through simulated environmental forces

The environmental fragmentation of plastic waste leads to the formation of micro- and nanoplastics (MNPs), which pose serious ecological and human health concerns. Despite increasing interest in their biological effects, many studies rely on artificial, uniform particles that fail to mimic the diverse physical and chemical characteristics of real-world MNPs. To address this limitation, we developed the Accelerated Plastic Aging in Suspension (APAS) system--a scalable, reproducible method that mimics natural aging processes by combining ultraviolet (UV) radiation, thermal stress, and mechanical shear to generate environmentally relevant MNPs from commonly used polymers. We used APAS to fragment polyethylene terephthalate (PET), polyamide 6 (Nylon), and polyacrylonitrile (PAN), and observed time-dependent degradation, including the spontaneous formation of nanoplastics (<100 nm). Flow cytometry revealed substantial increases in particle number and reductions in average particle size over 12 weeks. Imaging flow cytometry confirmed consistent generation of heterogeneous, irregular particles across replicate batches. High-resolution imaging via AFM, TEM, and SEM confirmed the presence of nanoplastics with textured and irregular morphologies. Chemical characterization showed APAS aging altered particle surface charge and induced polymer-specific changes in autofluorescence and Raman spectral profiles, consistent with oxidative surface modifications. Laser Direct Infrared (LDIR) imaging further confirmed structural and chemical changes in polymer spectra post-aging. Functionally, under physiologically relevant shear flow conditions, endothelial cells internalized APAS-generated PET MNPs at significantly higher levels than polystyrene (PS) beads of similar size. Uptake was enhanced particularly under oscillatory flow, highlighting the influence of particle physicochemical properties on cellular interactions. Together, these findings demonstrate the ability of the APAS system to produce complex and realistic MNPs for use in environmental and toxicological studies. The system enables generation of nanoplastics and supports more accurate modelling of biological exposure scenarios compared to conventional synthetic particles.

pharmacology and toxicology↗

bioRxiv2020

Machine Learning-based Biomarkers Identification and Validation from Toxicogenomics - Bridging to Regulatory Relevant Phenotypic Endpoints

High-throughput in vitro assays and AOP-based approach is promising for the assessment of health and ecotoxicological risks from exposure to pollutants and their mixtures. However, one of the major challenges in realization and implementations of the Tox21 vision is the urgent need to establish quantitative link between in-vitro assay molecular endpoint and in-vivo phenotypic toxicity endpoint. Here, we demonstrated that, using time series toxicomics in-vitro assay along with machine learning-based feature selection (MRMR) and classification method (SVM), an "optimal" number of biomarkers with minimum redundancy can be identified for prediction of phenotypic endpoints with good accuracy. We included two case studies for in-vivo carcinogenicity and Ames genotoxicity prediction with 20 selected chemicals including model genotoxic chemicals and negative controls, respectively, using an in-vitro toxicogenomic assay that captures real-time proteomic response data of 38 GFP-fused proteins of S. cerevisiae strains covering biomarkers indicative of all known DNA damage and repair pathways in yeast. The results suggested that, employing the adverse outcome pathway (AOP) concept, molecular endpoints based on a relatively small number of properly selected biomarker-ensemble involved in the conserved DNA-damage and repair pathways among eukaryotes, were able to predict both in-vivo carcinogenicity in rats and Ames genotoxicity endpoints. The specific biomarkers identified are different for the two different phenotypic genotoxicity assays. The top-ranked five biomarkers for the in-vivo carcinogenicity prediction mainly focused on double strand break repair and DNA recombination, whereas the selected top-ranked biomarkers for Ames genotoxicity prediction are associated with base- and nucleotide-excision repair. Current toxicomics approach still mostly rely on large number of redundant markers without pre-selection or ranking, therefore, selection of relevant biomarkers with minimal redundancy would reduce the number of markers to be monitored and reduce the cost, time, and complexity of the toxicity screening and risk monitoring. The method developed in this study will help to fill in the knowledge gap in phenotypic anchoring and predictive toxicology, and contribute to the progress in the implementation of tox 21 vision for environmental and health applications. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/423486v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@11bc876org.highwire.dtl.DTLVardef@105ebc2org.highwire.dtl.DTLVardef@1b91a63org.highwire.dtl.DTLVardef@1738486_HPS_FORMAT_FIGEXP M_FIG TOC Art C_FIG

pharmacology and toxicology↗

bioRxiv2019

Statistical approach for ...a test chemical is considered to be positive... in regulatory toxicology: Trend and pairwise tests

In regulatory toxicology an outcome is claimed positive when both a trend is significant and any pairwise test against control. Two statistical approaches are proposed: a joint Dunnett and Williams test (assuming the dose as a qualitative factor) and a joint test of the Tukey regression test and Dunnett test (assuming the dose as a quantitative covariate). Related R software is available.

pharmacology and toxicology↗

bioRxiv2021

Optimization of the TeraTox assay for preclinical teratogenicity assessment

Current animal-free methods to assess teratogenicity of drugs under development still deliver high numbers of false negatives, and more sensitive approaches of toxicity prediction are required. To address this issue, we characterized the TeraTox test, a newly developed multi-lineage differentiation assay for human teratogenicity prediction using 3D human induced pluripotent stem cells. TeraTox produces as primary output concentration-dependent data sets for each test compound on cytotoxicity and altered gene expression. These data are then fed into a prediction model based on an interpretable machine-learning approach. The final information obtained relates to the concentration-dependent human teratogenicity potential of drug candidates. We applied TeraTox to profile 33 approved pharmaceuticals and 12 proprietary drug candidates with known in vivo data. This way, it was possible to relate the test predictions to known human or animal toxicity. The TeraTox had an accuracy of 69% (specificity: 53%, sensitivity: 79%). It clearly performed better than two quantitative structure-activity relationship (QSAR) models and it had a higher sensitivity than the murine embryonic stem cell test (mEST) run in the same laboratory. By combining TeraTox and mEST data, the overall prediction accuracy was further improved. The knowledge on the pattern of altered gene expression may provide additional value in grouping toxicologically similar compounds and possibly deducing common modes of action. The assay will thus be a helpful additional tool in drug discovery, and the dataset provided here will be a valuable resource for the field of stem cell-based drug profiling.

pharmacology and toxicology↗

bioRxiv2025

UGT35B1 is the principal enzyme mediating nicotine glycosylation in Drosophila melanogaster

Nicotine is a plant-derived pyridine alkaloid with potent neurotoxic properties. A major pathway for detoxification of nicotine in mammals is via glucuronidation to produce nicotine N-glucuronide, but this process in insects remains poorly understood. Using mass spectrometry, we demonstrate that Drosophila melanogaster detoxifies nicotine through glycosylation, producing nicotine N-glycoside. Given that many new agrochemicals contain pyridine rings, we also investigated the metabolism of flonicamid and imidacloprid. We detected glycosylation of flonicamid, but not imidacloprid. A targeted RNAi screen across 21 UDP-glycosyltransferases (Ugts) identified Ugt35B1 as important for survival of nicotine exposure. CRISPR-based knockout of Ugt35B1 increases sensitivity to nicotine and flonicamid, but not to imidacloprid, nor to a structurally distinct neonicotinoid (thiamethoxam). Mass spectrometry of knockout and control flies confirms that Ugt35B1 glycosylates nicotine, its metabolite cotinine, and flonicamid. Together these findings establish Ugt35B1 as the principal UGT mediating nicotine detoxification in D. melanogaster, revealing a previously uncharacterized insect glycosylation pathway with potential implications for herbivory, insecticide detoxification and toxicology. Highlights- Drosophila detoxifies nicotine by glycosylation into nicotine N-glycoside. - A targeted RNAi screen identifies Ugt35B1 as critical for nicotine survival. - Ugt35B1 knockout sensitizes flies to nicotine and flonicamid, but not to imidacloprid or thiamethoxam. - First demonstration of an insect UGT mediating in vivo glycosylation of nicotine and cotinine.

pharmacology and toxicology↗

bioRxiv2026

Preclinical Safety Evaluation of Human Lactoferrin Alpha (Effera(R))

The preclinical safety of human-equivalent lactoferrin alpha (heqLF; effera(R)), produced by Komagataella phaffii, was evaluated to support its use as a food ingredient in infant formula and products for young children. Genotoxicity was assessed using a bacterial reverse mutation (Ames) assay in five strains of Salmonella typhimurium and Escherichia coli, and an in vitro micronucleus assay in TK6 cells. Both studies followed OECD guidelines and were conducted up to the recommended limit concentrations (5000 {micro}g/plate and 2000 {micro}g/mL, respectively). A 14-day non-GLP juvenile dose range-finding study and a 13-week GLP juvenile rat toxicity study with a 4-week recovery phase were conducted under ICH S11 guidance. Neonatal Sprague-Dawley rats received heqLF at 0, 1500, 3000, or 5000 mg/kg body weight/day by twice-daily oral gavage from postnatal day 7 to 98. Bovine lactoferrin (bLF) and whey protein at 5000 mg/kg body weight/day served as reference controls. heqLF was non-mutagenic and non-clastogenic in both genotoxicity assays. In the 13-week juvenile rat study, no heqLF-related mortality, clinical signs, developmental, neurobehavioral, or immune toxicity effects were observed. Minor, non-adverse renal findings consistent with high protein intake were observed and largely reversed during recovery. Clinical pathology parameters fully resolved during recovery. Toxicokinetic evaluation showed no systemic accumulation. Based on the absence of toxicologically relevant adverse findings, heqLF is well tolerated at doses up to 5000 mg/kg body weight/day, establishing a no observed adverse effect level (NOAEL) of 5000 mg/kg/day, the highest dose tested, and supporting its safety across intended populations from birth to adulthood.

pharmacology and toxicology↗

bioRxiv2026

Integrated Skin Sensitization Assessment Using Consensus Modelling and Tiered New Approach Methodology: A SaferSkin Case Study

The transition toward animal-free safety assessment of chemicals has accelerated the development of New Approach Methodologies (NAMs) for predicting skin sensitization. However, individual in silico models and experimental NAM assays frequently produce inconsistent or contradictory results, limiting their reliability when used in isolation. To address this challenge, we present a tiered integrated assessment framework implemented through the open source SaferSkin application, which enables systematic comparison and integration of multiple predictive models and experimental data within a transparent weight-of-evidence workflow. In this case study, a diverse set of 21 reference compounds was evaluated using a battery of in silico approaches, including the OECD QSAR Toolbox, VEGA, CASE Ultra and additional machine-learning models implemented within SaferSkin. The platform enables side-by-side comparison of predictions and integration of experimental data through Bayesian network models, allowing probabilistic updating of predictions as new evidence becomes available. Our results demonstrate that reliance on any single predictive model is insufficient for robust hazard identification due to frequent disagreement between models. In contrast, consensus interpretation across multiple modelling approaches combined with targeted experimental evidence substantially improves predictive confidence. The integrated weight-of-evidence framework showed strong concordance with reference classifications and was further supported by independent validation using the Pred-Skin Bayesian model. Importantly, the tiered workflow enables resolution of ambiguous cases. For example, lower-tier predictions for ethyl (2E,4Z)-deca-dienoate were inconsistent across models, whereas targeted third-tier testing using the SENS-IS assay identified the compound as a strong sensitiser (GHS Category 1A). Overall, this study demonstrates how integrated modelling, Bayesian evidence updating and targeted NAM testing can reduce uncertainty in skin sensitization assessment. The SaferSkin framework provides a transparent and reproducible approach for implementing Next Generation Risk Assessment (NGRA) strategies and supports the development of animal-free regulatory toxicology and Safe-and-Sustainable-by-Design chemical innovation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/711911v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@196a52eorg.highwire.dtl.DTLVardef@13690a6org.highwire.dtl.DTLVardef@1528703org.highwire.dtl.DTLVardef@11e05d2_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

pharmacology and toxicology↗

bioRxiv2021

Improving QSAR Modeling for Predictive Toxicology using Publicly Aggregated Semantic Graph Data and Graph Neural Networks

Quantitative Structure-Activity Relationship (QSAR) modeling is the most common computational technique for predicting chemical toxicity, but a lack of methodological innovations in QSAR have led to underwhelming performance. We show that contemporary QSAR modeling for predictive toxicology can be substantially improved by incorporating semantic graph data aggregated from open-access public databases, and analyzing those data in the context of graph neural networks (GNNs). Furthermore, we introspect the GNNs to demonstrate how they can lead to more interpretable applications of QSAR, and use ablation analysis to explore the contribution of different data elements to the final models performance.

pharmacology and toxicology↗

bioRxiv2024

Efficient analysis of toxicity and mechanism of food contaminants using network toxicology and molecular docking strategy: A Case Study of Aflatoxin B1

The present study aims to promote network toxicology and molecular docking strategies for the efficient evaluation of the toxicity of food contaminants. With the example of liver injury induced by the food contaminant Aflatoxin B1, this study effectively investigated the putative toxicity of food contaminants and the potentially molecular mechanisms. Initially, we obtained a preliminary overview of the toxicity of Aflatoxin B1 by using the ProTox-II and ADMETlab 2.0 databases. Subsequently, it was possible to identify 156 potential targets associated with Aflatoxin B1 and liver injury by using the ChEMBL, SwissTargetPrediction, GeneCards and DisGeNET databases. These were further refined by the STRING 5.0 database and Cytoscape 3.9.0 software for 23 core targets, including AKT1, SRC and EGFR. Then, GO and KEGG pathway analyses performed by Metascape database indicated that the core targets of Aflatoxin B1-induced hepatotoxicity were mainly enriched in cancer-related signalling pathways. Speedy molecular docking using Quick Vina confirmed the strong binding energy between Aflatoxin B1 and the core targets. In summary, Aflatoxin B1 may induce liver injury by regulating cell proliferation, cell survival, cell growth, cellular immune responses, and cellular signalling cascade responses in hepatocytes. We have provided a theoretical basis for understanding the molecular mechanism of Aflatoxin B1 hepatotoxicity and for the prevention and treatment of Aflatoxin B1-induced cancers in food contaminants. Furthermore, our network toxicology and molecular docking methods also provide an effective method for the rapid evaluation of the toxicity of food contaminants, which effectively solves the cost and ethical problems associated with the use of experimental animals. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/574998v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@ba292borg.highwire.dtl.DTLVardef@1e4e118org.highwire.dtl.DTLVardef@1760424org.highwire.dtl.DTLVardef@10a11ad_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

Evaluation of toxicological mechanisms of ochratoxin-A in human primary proximal tubule epithelial cells

Ochratoxin-A (OTA) is a ubiquitous mycotoxin contaminant in food products and a known nephrotoxin. OTA is hypothesized to be a potential environmental agent causing chronic kidney disease of unknown etiology (CKDu), however the mechanism of OTA toxicity in the human kidney remains elusive. This study aims to elucidate OTA-induced molecular toxicological pathways using primary human proximal tubule epithelial cells (PTECs). We demonstrated that exposure to OTA (10 M) induces over 7000 differentially expressed genes, including key regulators of mitochondrial fission and fusion. This was confirmed at the cellular level by confocal microscopy, where a breakdown of the mitochondrial network was observed at 100 nM OTA. Crucially, OTA was found to significantly induce reactive oxygen species (mROS) and inhibit basal mitochondrial oxidative phosphorylation as well as glycolysis through measurements of oxygen consumption rate and extracellular acidification, indicating reduced cellular energetics and mitochondrial toxicity. The previously reported downregulation of NRF2 target antioxidant response elements was not able to be recovered with co-administration of NRF2 agonists, sulforaphane or tert-butylhydroquinone, suggesting a possible mechanism of inhibition of NRF2 nuclear translocation or DNA binding. In conclusion, we demonstrate that OTA induces oxidative stress, mitochondrial dysfunction, and reduced ATP production, leading to a senescent-like state in PTECs characteristic of renal disease progression. These findings provide insight into early toxicological endpoints induced by OTA which have been established as pathophysiological changes involved in chronic kidney disease. HighlightsO_LIOTA exposure suppresses oxidative phosphorylation and glycolysis C_LIO_LIOTA exposure disrupts mitochondrial fission and fusion C_LIO_LIOTA induced mitochondrial ROS C_LIO_LIEarly mitochondrial stress may underlie OTA-associated CKDu risk C_LI

pharmacology and toxicology↗