Drug and Chemical Toxicology最新文献

Cigarette smoking (CS) was reported to induce the risk of renal diseases. However, heated tobacco product (HTP), a modified risk tobacco product, was claimed to reduce exposure risk, its health risk of kidney was still unclear. In this study, subchronic inhalation toxicity of HTP aerosols for 90 days was performed to assess its health risk of kidney. The nose-only exposure experiments were performed with SD rats. All the rats were randomly divided into sham, HTP (HTP_10, HTP_23, and HTP_50), and CS (Cig_23) groups. After exposure, the blood and kidney were prepared to detect its redox state, biomarkers in the early injury, apoptosis, and histopathology. The results showed that HTP and cigarette smoke both induced the expression of biomarkers including kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, interleukin 18, and oxidative stress. For biochemical markers associated with kidney function, CS induced increased creatinine and urea for female rats and uric acid decreased, while HTP exposure only induced the upregulation of creatinine. Moreover, no obvious apoptosis and pathology of kidney were observed after HTP exposure, which indicated that HTP exposure may induce some biomarkers in the early stage of kidney injury without more serious changes. Overall, these results suggested that HTP with high concentration exposure showed potential slight health risks of kidney.

5-fluorouracil (5-FU) is an important chemotherapeutic agent that has been used alone or in combination with other chemotherapeutics for years in the treatment of various malignancies. However, as with other chemotherapeutic agents, the disadvantage of 5-FU is that it damages healthy cells as well as cancer cells. Natural compounds are the first option that comes to mind to reduce and/or prevent undesirable side effects of chemotherapeutics. In this study, we aimed to determine the effects of Juglans regia extract (JR), whose antioxidant, anti-inflammatory, anti-diabetic, and antimicrobial effects were previously determined, on 5-FU-induced autophagy, oxidative stress, and apoptosis after its constituents were determined by LC-MS/MS. Experimental groups were formed as Control (C), JR, 5-FU, and JR + 5-FU. Rats were pretreated with JR at a dose of 200 mg/kg for seven days, and on the eighth day, a single dose of 100 mg/kg 5-FU was administered intraperitoneally to the JR + 5-FU and 5-FU groups. 5-FU disturbed the oxidant-antioxidant balance by increasing Keap1, TOS, and 8-OHdG levels and decreasing TAS levels and triggered cellular autophagy and apoptosis by increasing LC3B, Bax, and Caspase-3 levels and decreasing Bcl-2. JR pretreatment was shown to have modulating effects on the Keap1/Nrf2 pathway in the reorganization of the oxidant-antioxidant balance, to show anti-apoptotic activity, and to partially alleviate autophagy. JR's bioactive components were shown to alleviate oxidative stress and associated DNA damage via Keap1/Nrf2 and also attenuate fluorouracil-induced kidney damage by reducing autophagy and apoptosis, two important forms of programmed cell death, and have a promising potential against nephrotoxicity.

Tamoxifen (TAM), the gold standard treatment for hormone-responsive breast cancer, is the most widely used Selective Estrogen Receptor Modulator (SERM). Based on the premise that subchronic oral administration of TAM may induce neurotoxic effects, we hypothesize that TAM triggers maladaptive behavior in intact female Wistar rats. The contribution of hippocampal apoptosis, inflammation, and of the hypothalamic-pituitary-adrenal (HPA) axis parameters to the maladaptive behavior was also investigated. Intact female rats (60-day-old) were treated intragastrically with TAM (0.25 and 2.5 mg/kg) for 59 days. Behavioral tests were conducted from day 120 to 125, after which the rats were euthanized. Different phenotypic manifestations of maladaptive behavior were observed in female rats treated with TAM. Psychomotor agitation and anxiety-like behavior appeared only in those receiving the lowest TAM dose. In contrast, anhedonia was observed only in female rats treated with the highest TAM dose. Behaviors, such as despair, apathy, and thigmotaxis were observed in female rats treated with both TAM doses. In ex vivo analysis, inflammatory markers in hippocampus of hormonally intact female rats were found to vary depending on the TAM dose. While the relative weight of the uterus decreased in TAM-exposed rats, only the highest TAM dose increased plasma corticosterone and hippocampal glucocorticoid receptor levels. Only the lowest TAM dose increased hippocampal p75NTR and Bax levels and decreased Bcl2, apoptosis markers. Summarizing, TAM subchronic oral administration, dependent on the dose, induced maladaptive behavior in intact female rats, which were associated with the hippocampal modulation of apoptosis, HPA axis markers, and inflammation.

Dapagliflozin (DAPA) is a sodium-glucose cotransporter (SGLT) inhibitor used in the treatment of type 2 diabetes mellitus. DAPA, used in the treatment of type 2 diabetes mellitus (T2DM), has been shown to cause liver damage in clinical studies, and has raised concerns due to drug-related breast and bladder cancer cases. However, due to the lack of information regarding its potential effects on humans, genotoxicity assessments of DAPA are necessary, and its use should be reconsidered following these assessments. For all these reasons, this study aimed to determine the possible cytotoxic and genotoxic effects of DAPA on Drosophila melanogaster. Four DAPA concentrations (0.1, 1, 5, and 10 mM) were assessed for behavioral toxicity and DNA damage detection using the Comet assay. Furthermore, the genotoxic potential of three DAPA concentrations (0.225, 0.45, and 0.9 mM) was assessed using the Drosophila SMART assay. According to the results of behavioral toxicity experiments, changes in larval weight, larval crawling, negative geotaxis, and adult individual formation success at specific doses were found to be statistically significant. However, changes in pupal formation success, pupal position, and adult individual weight were not found to be statistically significant. In the Comet test results, changes were found in all treatment groups compared to the control group, while in the SMART test, only the frequency increases in the 0.9 mM treatment group were found to be statistically significant. Molecular techniques are needed to explain the exact mechanism of the changes observed in the test systems.

Citrus maxima (Burm). Merr. (CM) has been extensively documented worldwide for its diversified ethno-pharmacological activities. Although the seeds have been previously evaluated for their anxiolytic, analgesic and anti-inflammatory properties, they have not been extensively studied, unlike other plant parts. This study investigates the phytochemical composition and oral toxicity profile of ethanolic seed extract of CM (EESCM) in male and female balb/c mice. TPC and HPLC analyses confirmed the presence of phytoconstituents like naringin, caffeic acid, and hesperidin. Acute toxicity testing involved oral administration of EESCM at 1000, 2000, and 3000 mg/kg body weight (B.W.) over 14 days, revealing no observable toxicity signs. In the subacute study, mice received doses of 300, 600, and 900 mg/kg for 28 days. No significant alterations were observed in food and water intake or most hematological and biochemical parameters, except AST elevation in both sexes. There were no major histological manifestations of tissue damage in 300 and 600 mg/kg, but some changes were detected in the liver, kidney, and spleen at 900 mg/kg. The findings suggested that EESCM is reasonably nontoxic in mice. This effect could be due to the presence of potent antioxidants, which could be beneficial for providing therapeutic activities for the seeds in the future.

Rotenone, an insecticide, and herbicide has been associated with various environmental and health concerns. This study investigates the molecular alterations in rotenone-treated murine pancreatic beta cells, using untargeted metabolomics based on liquid chromatography-mass spectrometry. We established a model mimicking rotenone toxicity in MIN6 cells and observed decreased insulin secretion despite no significant loss of cellular viability. Our untargeted metabolomics analysis revealed a decrease in 19 metabolites and an increase in 62 metabolites following exposure to rotenone. Mapping these changes onto metabolic pathways, we found that purine metabolism underwent significant alterations. Critical metabolites in this pathway, including adenine, adenosine monophosphate, guanine, and others, exhibited a substantial increase upon rotenone treatment. This study underscores the utility of untargeted metabolomics for investigating molecular alterations due to rotenone exposure. It further highlights rotenone's significant impact on purine metabolism, providing potential insights into the mechanisms of rotenone-associated diabetes risk.

The role of environmental pollutants as risk factors for Alzheimer's disease (AD) and related neurodegenerative pathologies necessitates mechanistic investigation. Evidence implicates brominated flame retardants (BFRs)-decabromodiphenyl ethane (DBDPE)-in AD pathogenesis, though their molecular mechanisms remain inadequately elucidated. To address this challenge, we combined multiple cross-disciplinary methods (network toxicology, machine learning [ML], molecular docking, molecular dynamics [MD] simulations, and Mendelian randomization [MR] analysis) to systematically delineate DBDPE-induced AD pathogenesis. Initial screening of the SwissTargetPrediction database and GSE132903 dataset identified 47 overlapping DBDPE-AD targets. Subsequent protein-protein interaction (PPI) network analysis refined these to 42 high-confidence targets. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed association of core targets with metabolic pathways and neuroactive ligand-receptor interactions. Three core targets were prioritized using ML framework. Molecular docking confirmed strong binding affinities between DBDPE and the core targets. Given PLAU's exceptional binding energy, we conducted MD simulations to validate complex stability and characterize binding-site interactions. Finally, MR analysis established causal links between PLAU and AD susceptibility. In summary, this study establishes a comprehensive theoretical framework for understanding the molecular mechanisms of DBDPE-induced AD and provides valuable insights for developing preventive and therapeutic strategies targeting AD associated with DBDPE exposure.

This study explores the pharmacological synergy between Curcuma longa (turmeric) compounds and cisplatin in ovarian cancer treatment, focusing on overcoming drug resistance and minimizing toxicity. Using bibliometric analysis with tools like Publish or Perish and VOSviewer, the research identifies significant novelty in this field. Active compounds of C. longa were screened for drug-likeness and oral bioavailability through Molsoft and SwissADME, while potential therapeutic targets were predicted using databases such as SwissTargetPrediction, GeneCards, and DrugBank. Network pharmacology and PPI analysis via Cytoscape and STRING, along with GO and REACTOME enrichment via DAVID. In the pharmacological network, quercetin, cytosolic tRNA aminoacylation, and ALOX5 (arachidonate 5-lipoxygenase) are the substances, targets, and pathways with the highest degrees. The PPI target with the highest degree is TP53 (tumor protein p53). GO enrichment (BP, CC, MF) and REACTOME are cytosolic tRNA aminoacylation, tRNA aminoacylation, and mucopolysaccharidoses. Docking simulations showed strong binding between campesterol and CDK2 (-10.8 kcal/mol) as well as campesterol and TP53 (-9.7 kcal/mol). These results suggest that C. longa compounds could enhance cisplatin's anticancer activity, reduce toxicity, and help overcome drug resistance in ovarian cancer therapy. The findings highlight the potential for natural, polyphenol-rich agents to complement chemotherapy and improve treatment outcomes.

This in vivo study was conducted to determine the effects of a single exposure to 7,12-dimethylbenzo[a]anthracene (DMBA) on mouse skin at several end points throughout a 24-hour exposure period. The protective effects of calcium glucarate (CAG), butyric acid (BA), and nicotinamide (NA) were also assessed in terms of DNA synthesis, hypertrophy, and cell proliferation markers, including the expression of the inflammation-related gene cyclooxygenase-2 (Cox-2), proliferating cell nuclear antigen (PCNA), cellular myelocytomatosis oncogene (c-Myc), and ornithine decarboxylase (ODC). Briefly, mouse skin was topically treated with DMBA. Additionally, the DMBA-treated area received topical applications of BA, NA, or CAG, either separately or in combination. Mice were sacrificed at the end of 4, 8, 16 and 24 hours after DMBA treatment. To access DNA synthesis, the [methyl-3H] thymidine incorporation test was performed. Reverse transcription-PCR (RT-PCR) and Western blotting were employed to assess gene expression at the mRNA and protein levels. As early as 4 hours after exposure, DMBA caused increased DNA synthesis and consequent hypertrophy, which was followed by overexpression of ODC, c-Myc, PCNA, and Cox-2. It gradually decreases at the end of the 24-hour period following exposure to DMBA, after peaking at the end of the 16-hour period. It was identified that DMBA-induced alterations could be prevented by BA, NA, and CAG, but that their combination worked best. A novel and improved method of managing skin hypertrophy with natural agents is made possible by the combined enhanced preventative effects of BA, NA, and CAG.

Per- and polyfluoroalkyl substances (PFAS) are widely used in various industries but pose significant ecological and human health risks, particularly to the nervous system. However, the underlying neurotoxic mechanisms remain poorly understood. This study combines network toxicology and machine learning to explore these mechanisms. Using ADMETLAB 3.0, we assessed the environmental toxicity of six common PFAS and identified their potential targets using online tools. A compound-target interaction network was built, followed by protein-protein interaction (PPI) and KEGG pathway analyses to investigate toxicological pathways. Core targets were selected through machine learning, and differential gene expression was analyzed using transcriptomic data. Molecular docking simulations predicted binding affinities between PFAS and their core targets, while molecular dynamics simulations on key complexes were performed using Gromacs 2023.2 and the Charmm36 force field. PFDS showed the highest bioconcentration factors (BCF), while PFOA demonstrated the greatest toxicity. We identified 62 intersecting targets, with PTGS2, MMP9, and ESR1 being central in the PPI network. Transcriptomic analysis revealed 1,077 differentially expressed genes (DEGs), highlighting associated biological processes and pathways. The random forest model identified 20 core genes, with 9 significantly differentially expressed in the PFAS-treated group. Molecular docking suggested potential interactions between the compounds and core targets, and molecular dynamics simulations further supported the stability of the complexes under physiological conditions. This study provides valuable insights into the neurotoxic mechanisms of PFAS, enhancing our understanding of their impact on the nervous system.