Search Results (381)

This study investigated the molecular mechanisms by which phthalates induce depression, utilizing network toxicology and molecular docking techniques. By integrating the TargetNet, GeneCards, and PharmMapper databases, 658 potential target genes of phthalates were identified. Additionally, 5433 depression-related targets were retrieved from the GeneCards and OMIM databases. Comparative analysis revealed 360 common targets implicated in both phthalate action and depression. A Protein-Protein Interaction (PPI) network was constructed using the STRING database. Subsequently, the CytoHubba plugin (employing the MCC algorithm) within Cytoscape was used to screen the network, identifying the top 20 hub genes. These core genes include AKT1, CASP3, TNF, TP53, BCL2, and IL6, among others. Validation on the GEO dataset (GSE23848) revealed that the expression of multiple core genes was significantly upregulated in patients with depression (p < 0.05). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that phthalates mainly regulate biological processes such as extracellular stimulus response, lipopolysaccharide metabolism, and chemical synaptic transmission. Depression is mediated by the AGE-RAGE signaling pathway (a complication of diabetes), lipids and atherosclerosis, Endocrine resistance, and the PI3K-Akt signaling pathway. Molecular docking confirmed that phthalates have strong binding activity with key targets (CASP3, TNF, TP53, BCL2, IL6). These findings present a novel paradigm for evaluating the health risks posed by environmental pollutants. Full article

Background/Objectives: Cocaine is a widely used illicit stimulant with significant toxicity. Despite its clinical relevance, the broader metabolic alterations associated with cocaine use remain incompletely characterized. This study aims to identify novel biomarkers for cocaine exposure by applying untargeted metabolomics to retrospective urine drug screening data. Methods: We conducted a retrospective analysis of a raw mass spectrometry (MS) dataset from urine comprehensive drug screening (UCDS) from 363 patients at the University of Pittsburgh Medical Center Clinical Toxicology Laboratory. The liquid chromatography–quadrupole time-of-flight mass spectrometry (LC-qToF-MS) data were preprocessed with MS-DIAL and subjected to multiple statistical analyses to identify features significantly associated with cocaine-enzyme immunoassay (EIA) results. Significant features were further evaluated using MS-FINDER for feature annotation. Results: Among 14,883 features, 262 were significantly associated with cocaine-EIA results. A subset of 37 more significant features, including known cocaine metabolites and impurities, nicotine metabolites, norfentanyl, and a tryptophan-related metabolite (3-hydroxy-tryptophan), was annotated. Cluster analysis revealed co-varying features, including parent compounds, metabolites, and related ion species. Conclusions: Features associated with cocaine exposure, including previously underrecognized cocaine metabolites and impurities, co-exposure markers, and alterations in an endogenous metabolic pathway, were identified. Notably, norfentanyl was found to be significantly associated with cocaine -EIA, reflecting current trends in illicit drug use. This study highlights the potential of repurposing real-world clinical toxicology data for biomarker discovery, providing a valuable approach to identifying exposure biomarkers and expanding our understanding of drug-induced metabolic disturbances in clinical toxicology. Further validation and exploration using complementary analytical platforms are warranted. Full article

The rapid development of the nuclear industry and mining has increased environmental radioactive contamination, posing potentially ecological risks and health threats to humans. Uranium compounds are known to exhibit selective nephrotoxicity, but their toxicological processes and mechanisms still remain poorly understood and controversial. In this study, the uranyl-induced toxicity in human renal tubular epithelial cells (HK-2) were explored using flow cytometry, DAPI staining, and comet assays. Our results demonstrate that uranium exposure primarily triggers apoptosis. Kyoto Encyclopedia of Genes and Genomes pathway enrichment and protein–protein interaction (PPI) analyses revealed significant associations with DNA damage. Moreover, aberrant expression of ABC transporters (e.g., ABCB7) and mitochondrial-related proteins confirms uranium-induced mitochondrial dysfunction. Gene Ontology functional annotation implicated extrinsic apoptotic signaling pathways in uranium-induced cell death. The downregulation of the UBL5 protein also pointed to endoplasmic reticulum stress-mediated apoptosis. In summary, uranium exposure can induce the apoptosis of HK-2 cells through intrinsic pathways by damaging DNA and mitochondria and disrupting protein synthesis, with secondary contributions from endoplasmic reticulum stress and extrinsic apoptotic signaling. Full article

This study comprehensively analysed the scientific production of the extraction, characterisation, and toxicological risk of resistant starches obtained from agro-industrial by-products. Articles indexed in the Scopus database between 2015 and 2025 were analysed. The results showed a progressive increase in publications led by Chinese institutions, the most notable being Jiangnan University. Most of the studies were published in high-impact journals, with the International Journal of Biological Macromolecules standing out, followed by Carbohydrate Polymers and Food Chemistry, all in the first quartile. Most studies focused on extraction methods (physical, chemical, and mechanical) and starch characterisation (morphological, structural, molecular, physicochemical, and functional). Emerging trends are directed towards innovative applications such as functional foods. However, the risks associated with contaminants in reusing agro-industrial by-products have not been adequately explored, showing an important gap in the current scientific literature. In this context, future research should focus on evaluating toxicological risks derived from these processes, considering the presence and behaviour of heavy metals, pesticides, and mycotoxins, as well as the possible migration of chemical compounds generated during extraction. Full article

Monk fruit extract (Siraitia grosvenorii, MFE) is a natural, non-caloric sweetener known for its intense sweetness, antioxidant properties, and potential metabolic health benefits. While certain aqueous monk fruit decoctions are recognised as non-novel foods in the UK and Ireland due to significant pre-1997 consumption, the European Union (EU) has adopted a more cautious approach under the Novel Food Regulation (EU) 2015/2283. As of October 2024, only one specific aqueous extract of monk fruit has been authorised in the EU under Regulation (EU) 2024/2345, permitting its use in several food categories. However, highly purified mogrosides and non-aqueous extracts remain unapproved due to gaps in toxicological data and the absence of industry-led applications. This review systematically analyses the EU’s regulatory barriers, comparing MFE’s legal status with other approved non-caloric sweeteners such as steviol glycosides and erythritol, and examining regulatory frameworks in the EU, United States, United Kingdom, and China. Findings indicate that although 18 non-caloric sweeteners are currently authorised in the EU, regulatory constraints continue to hinder the broader approval of MFE, limiting innovation and the availability of natural sweeteners for consumers. Harmonising regulations, leveraging international safety assessments, and promoting industry engagement are recommended to advance MFE’s authorisation and support sustainable food innovation in the EU. Addressing these challenges is crucial to ensure that European consumers and industry can benefit from safe, innovative, and health-promoting alternatives to sugar, aligning food policy with broader public health goals and sustainability commitments. Full article

Breast cancer, a highly prevalent malignancy among women, continues to pose a significant global health challenge, as conventional therapies are often limited by adverse effects. This study developed and evaluated nanostructured lipid carriers (NLCs) encapsulating fatty acid amides (FAAs) semi-synthesized from andiroba oil and combined with silk fibroin (SF) as a novel therapeutic strategy. Methods: FAAs were synthesized via direct amidation and characterized by GC-MS, FT-IR, and ¹³C NMR. These fatty acid amides were then incorporated into NLCs containing SF. The formulation was evaluated for its physicochemical stability, cell selectivity, and cytotoxicity against 4T1 murine breast cancer cells and healthy human fibroblasts. Results: The NLC-FAA/SF formulation exhibited physicochemical stability (average particle size: 136.9 ± 23.6 nm; zeta potential: −8.3 ± 12.0 mV; polydispersity index: 0.19 ± 0.04), indicating a monodisperse and stable system. In vitro cytotoxicity assays demonstrated high selective activity against 4T1 murine breast cancer cells (IC₅₀ = 0.18 ± 0.06 μg/mL) and negligible toxicity to healthy human fibroblasts. Molecular docking studies revealed favorable interactions between the FAAs and cannabinoid receptors CB1 and CB2, with unsaturated FAAs showing higher binding scores and stability, suggesting their potential as cannabinoid receptor ligands. These findings highlight NLC-FAA/SF as a promising, selective, and effective nanoplatform for breast cancer treatment, warranting further investigation into its mechanism of action and in vivo efficacy. Full article

This study aimed to evaluate the anticancer activity of lamellar alkaloid derivatives extracted from the tunicate Didemnum abradatum from Moucha Island (Djibouti), focusing on their antiviability against human cell lines and using biocomputational analyses via the Integrated Biomolecular Profiling and Mechanism Evaluation (IBProME) method to understand their mechanisms of action. Two alkaloids were isolated, lamellarin D and lamellarin T, whose structures were confirmed by state-of-the-art analytical techniques. Cell viability tests were performed on PC3, A549 and JIMT-T1 cell lines, and IBProME analyses were used to predict their interactions with p53 protein and evaluate their toxicological and pharmacokinetic profiles. The results showed that lamellarin D was particularly effective against prostate and lung cancer cells, with respective IC₅₀ values of 5.25 µg/mL and 8.64 µg/mL, close to those of doxorubicin. In contrast, lamellarin T showed less marked activity but remains promising. Computational analyses via IBProME highlighted differences in chemical reactivity between the two compounds, with lamellarin D being more reactive. Toxicity tests revealed that lamellarin D exhibited lower acute toxicity than lamellarin T. In terms of pharmacokinetic properties, both molecules showed low absorption and moderate bioavailability, although lamellarin T displayed more marked lipophilicity. These results suggest that lamellars, particularly lamellarin D, have therapeutic potential for the treatment of certain types of cancer. Full article

Tetrabromobisphenol A (TBBPA), a widely utilised brominated flame retardant, demonstrates toxicological effects in aquatic organisms. Tea polyphenols (TPs), natural compounds found in tea leaves, exhibit both antioxidant and anti-inflammatory activities. The kidney is one of the major metabolic organs in common carp and serves as a target organ for toxic substances. This study evaluated the therapeutic potential of TPs in mitigating TBBPA-induced nephrotoxicity in common carp. Common carp were exposed to 0.5 mg/L TBBPA in water and/or fed a diet supplemented with 1 g/kg TPs for 14 days. In vitro, primary renal cells were treated with 60 μM TBBPA and/or 2.5 μg/L TPs for 24 h. Methods included histopathology, TUNEL assay for apoptosis, ROS detection, and molecular analyses. Antioxidant enzymes (SOD, CAT) and inflammatory cytokines (IL-1β, IL-6, TNF-α) were quantified using ELISA kits. Results showed that TBBPA induced oxidative stress, and activated the ROS-PI3K/AKT-NF-κB pathway, thereby resulting in inflammatory responses. TBBPA upregulated apoptosis-related genes (Caspase-3, Bax, and Bcl-2) and induced apoptosis. TBBPA upregulated the expression of RIPK3/MLKL, thereby exacerbating necroptosis. TPs intervention significantly mitigated these effects by reducing ROS, suppressing NF-κB activation, and restoring antioxidant enzyme activities (SOD, CAT). Moreover, TPs attenuated apoptosis and necrosis in the carp kidney, thereby enhancing the survival ability and immunity of common carp. Full article

Hypothermia-related deaths present significant diagnostic challenges due to non-specific and often inconsistent autopsy findings. This study investigated the histological and immunohistochemical alterations associated with primary and secondary hypothermia in an experimental Rattus norvegicus model, focusing on the effects of benzodiazepine and alcohol ingestion. Twenty-one male rats were divided into three groups: control (K), benzodiazepine-treated (B), and alcohol-treated (A). After two weeks of substance administration, hypothermia was induced and multiple organ samples were analyzed. Histologically, renal tissue showed hydropic and vacuolar degeneration, congestion, and acute tubular injury across all groups, with no significant differences in E-cadherin expression. Lung samples revealed congestion, emphysema, and hemorrhage, with more pronounced vascular congestion in the alcohol and benzodiazepine groups. Cardiac tissue exhibited vacuolar degeneration and protein denaturation, particularly in substance-exposed animals. The spleen showed preserved architecture but increased erythrocyte infiltration and significantly elevated myeloperoxidase (MPO)-positive granulocytes in the intoxicated groups. Liver samples demonstrated congestion, focal necrosis, and subcapsular hemorrhage, especially in the alcohol group. Immunohistochemical analysis revealed statistically significant differences in MPO expression in both lung and spleen tissues, with the highest levels observed in the benzodiazepine group. Similarly, CK7 and CK20 expression in the gastroesophageal junction was significantly elevated in both alcohol- and benzodiazepine-treated animals compared to the controls. In contrast, E-cadherin expression in the kidney did not differ significantly among the groups. These findings suggest that specific histological and immunohistochemical patterns, particularly involving pulmonary, cardiac, hepatic, and splenic tissues, may help differentiate primary hypothermia from substance-related secondary hypothermia. The study underscores the value of integrating toxicological, histological, and molecular analyses to enhance the forensic assessment of hypothermia-related fatalities. Future research should aim to validate these markers in human autopsy series and explore additional molecular indicators to refine diagnostic accuracy in forensic pathology. Full article

This study explores how aristolochic acid I (AAI) drives hepatocellular carcinoma (HCC). We first employ network toxicology and machine learning to map the key molecular target genes. Next, our research utilizes molecular docking to evaluate how AAI binds to these targets, and finally confirms the stability and dynamics of the resulting complexes through molecular dynamics simulations. We identified 193 overlapping target genes between AAI and HCC through databases such as PubChem, OMIM, and ChEMBL. Machine learning algorithms (SVM-RFE, random forest, and LASSO regression) were employed to screen 11 core genes. LASSO serves as a rapid dimension-reduction tool, SVM-RFE recursively eliminates the features with the smallest weights, and Random Forest achieves ensemble learning through decision trees. Protein–protein interaction networks were constructed using Cytoscape 3.9.1, and key genes were validated through GO and KEGG enrichment analyses, an immune infiltration analysis, a drug sensitivity analysis, and a survival analysis. Molecular-docking experiments showed that AAI binds to each of the core targets with a binding affinity stronger than −5 kcal mol⁻¹, and subsequent molecular dynamics simulations verified that these complexes remain stable over time. This study determined the potential molecular mechanisms underlying AAI-induced HCC and identified key genes (CYP1A2, ESR1, and AURKA) as potential therapeutic targets, providing valuable insights for developing targeted strategies to mitigate the health risks associated with AAI exposure. Full article

Fungicides are compounds with potentially toxic effects on the human body, but the molecular mechanisms of their action have not yet been explained. The effect of cyprodinil on cell viability, apoptosis level, cell membrane function, cell morphology and expression of antioxidant enzyme genes in the A-375 and DLD-1 cell lines was examined. The cell lines were selected because they can be an excellent in vitro model of neoplastic changes occurring in the skin and large intestine after exposure to a fungicide. The fungicide selected for the study is commonly used in Poland to protect crops against fungi. Our results showed that the tested compound increased cell viability and proliferation, probably activated by mechanisms related to oxidative stress. Cyprodinil caused an increase in glutathione level (in A-375 by about 37% and in DLD-1 by about 28%) and oxidative stress enzymes activity, but not in apoptosis level. Its membrane interactions and its penetration into cells was concentration dependent. It is worth emphasizing that the novelty of our work lies in the use of non-traditional toxicological methods based on molecular analyses using human cell lines. This allowed us to demonstrate not only the toxicity of a single substance but also its behavior within cellular structures. Our findings suggest that cyprodinil may have tumor-promoting properties in skin and colorectal cancer cells. Full article

Perfluoroalkyl substances (PFASs) possess immunosuppressive properties. However, their association with rheumatoid arthritis (RA) risk remains inconclusive across epidemiological studies. This study integrates population-based and mechanistic evidence to clarify the relationship between PFAS exposure and RA. We analyzed 8743 U.S. adults from the NHANES (2005–2018), assessing individual and mixed exposures to PFOA, PFOS, PFNA, and PFHxS using multivariable logistic regression, Bayesian kernel machine regression, quantile g-computation, and weighted quantile sum models. Network toxicology and molecular docking were utilized to identify core targets mediating immune disruption. The results showed that elevated PFOA (OR = 1.63, 95% CI: 1.41–1.89), PFOS (OR = 1.41, 1.25–1.58), and PFNA (OR = 1.40, 1.20–1.63) levels significantly increased RA risk. Mixture analyses indicated a positive joint effect (WQS OR = 1.06, 1.02–1.10; qgcomp OR = 1.26, 1.16–1.38), with PFOA as the primary contributor. Stratified analyses revealed stronger effects in females (PFOA Q4 OR = 3.75, 2.36–5.97) and older adults (≥60 years). Core targets included EGFR, SRC, TP53, and CTNNB1. PFAS mixtures increase RA risk, dominated by PFOA and modulated by sex/age. These findings help reconcile prior contradictions by identifying key molecular targets and vulnerable subpopulations, supporting regulatory attention to PFAS mixture exposure. Full article

Background/Objectives: The effect of diet on maternal and infant genetic levels has been reported in the literature. Diet-associated DNA damage, such as the presence of micronuclei (MN), may be related to an increased risk of developing chronic diseases such as cancer. There is particular concern regarding this damage during pregnancy, as it may affect the newborn (NB). Thus, this review aims to summarize the primary evidence of the impact of diet on the frequency of MN in the mother–infant population. Methods: Five databases (PubMed, Embase, Web of Science, Scopus, and ScienceDirect) were used to search for observational studies. Google Scholar and manual searching were required to perform the “gray literature” search. Results: The search strategy retrieved 1418 records. Of these, 13 were read in full and 5 were included in the review. Most studies were of the cohort type (n = 4) and were carried out in the European region. A total of 875 pregnant women and 238 newborns were evaluated. Despite insufficient evidence to confirm that diet changes the frequency of MN, the included studies found possible effects from the consumption of fried red meat and processed meats and the adequate consumption of vegetables and polyunsaturated fats. Conclusions: Future research is needed in order to understand the effects of diet on genetic stability and to obtain evidence to help plan public policies on food and nutrition or reinforce protective dietary patterns for this and future generations. Full article

Over the past years, increasing attention has been drawn to the adverse effects of agricultural pesticide use on pollinators, with honeybees being especially vulnerable. The aim of this study was to evaluate the levels of residues detectable and/or quantifiable of neonicotinoid pesticides and other pesticides in biological materials (bees, bee brood, etc.) and beehive products (honey, pollen, etc.) applied as seed dressings in rapeseed and sunflower plants in two growing seasons (2020–2021) in fields located in three agro-climatic regions in Romania. The study involved the comparative sampling of hive products (honey, pollen, adult bees, and brood) from experimental and control apiaries, followed by pesticide residue analysis in an accredited laboratory (Primoris) using validated chromatographic techniques (LC-MS/MS and GC-MS). Toxicological analyses of 96 samples, including bees, bee brood, honey, and pollen, confirmed the presence of residues in 46 samples, including 10 bee samples, 10 bee brood samples, 18 honey samples, and 8 pollen bread samples. The mean pesticide residue concentrations detected in hive products were 0.032 mg/kg in honey, 0.061 mg/kg in pollen, 0.167 mg/kg in bees, and 0.371 mg/kg in bee brood. The results highlight the exposure of honeybee colonies to multiple sources of pesticide residue contamination, under conditions where legal recommendations for the controlled application of agricultural treatments are not followed. The study provides relevant evidence for strengthening the risk assessment framework and underscores the need for adopting stricter monitoring and regulatory measures to ensure the protection of honeybee colony health. Full article

Copper pyrithione (CuPT), an emerging biocide used in ship antifouling coatings, may accumulate in marine sediments and pose risks to non-target organisms. However, current research on CuPT toxicity remains limited. Litopenaeus vannamei, one of the world’s most important aquaculture shrimp species, relies heavily on its hepatopancreas for energy metabolism, detoxification, and immune responses. Due to their benthic habitat, these shrimps are highly vulnerable to contamination in sediment environments. This study investigated the toxicological response in the hepatopancreas of L. vannamei exposed to CuPT (128 μg/L) for 3 and 48 h. Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) fluorescence staining revealed increased apoptosis, deformation of hepatic tubule lumens, and the loss of stellate structures in the hepatopancreas after CuPT 48 h exposure. A large number of differentially expressed genes (DEGs) were identified by transcriptomics analysis at 3 and 48 h, respectively. Most of these DEGs were related to detoxification, glucose transport, and immunity. Metabolomic analysis identified numerous significantly different metabolites (SDMs) at both 3 and 48 h post-exposure, with most SDMs associated with energy metabolism, fatty acid metabolism, and related pathways. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of metabolomics and transcriptome revealed that both DEGs and SDMs were enriched in arachidonic acid metabolism, fatty acid biosynthesis, and glycolysis/gluconeogenesis pathways at 3 h, while at 48 h they were enriched in the starch and sucrose metabolism, amino sugar and nucleotide sugar metabolism, and galactose metabolism pathways. These results suggested that CuPT disrupts the energy and lipid homeostasis of L. vannamei. This disruption compelled L. vannamei to allocate additional energy toward sustaining basal physiological functions and consequently caused the accumulation of large amounts of reactive oxygen species (ROS) in the body, leading to apoptosis and subsequent tissue damage, and ultimately suppressed the immune system and impaired the health of L. vannamei. Our study elucidates the molecular mechanisms of CuPT-induced metabolic disruption and immunotoxicity in L. vannamei through integrated multi-omics analyses, providing new insights for ecological risk assessment of this emerging antifoulant. Full article