Toxicology Mechanisms and Methods最新文献

Foam cell formation is a critical pathological process that contributes significantly to the development of atherosclerosis, influenced by processes such as vascular senescence and autophagy-lysosomal pathways. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has recently received interest due to its role in foam cell formation, but its connection to senescence and autophagy are still not well defined. This research investigated the role of Nrf2 in modulating senescence and autophagy in foam cells using an in vitro model of THP-1-derived macrophage foam cells. The effect of siRNA-induced silencing of Nrf2 on intracellular lipids buildup, cholesterol efflux, and the activation of senescence and autophagy were analyzed. Our findings indicate that Nrf2 silencing reduced the formation of foam cells by lowering intracellular lipid accumulation and enhancing cholesterol efflux in THP-1 macrophages. Additionally, silencing of Nrf2 lead to a reduction in cellular senescence, reflected by reduced β-galactosidase activity and a decrease in the expression of senescence-associated secretory phenotype (SASP) markers (Matrix metalloproteinase-9 (MMP-9) and tumor necrosis factor (TNF-α)) expression. This is accompanied by activation of autophagy, as indicated by enhanced formation of autophagosome and LC3B expression. Furthermore, inhibiting the late stage of autophagy with hydroxychloroquine (HCQ) decreased cell viability, while early-stage autophagy inhibition using 3-Methyladenine (3-MA) had no significant effect. These results highlight the critical role of Nrf2 in controlling foam cell development, senescence, and autophagic processes, giving valuable insights into potential therapeutic targets for atherosclerosis.

Drug hepatotoxicity is one of the primary reasons for drug clinical trial failures and market withdrawals, with mitochondrial dysfunction being one of the mechanisms inducing drug hepatotoxicity. Manifestation of mitochondrial toxicity occurs when mitochondria are damaged or their functions are inhibited. This study introduces M3Hep, a novel multimodal framework that integrates SMILES, molecular graphs, and mitochondrial toxicity through a masking strategy to improve hepatotoxicity prediction. A total of 8,459 mitochondrial toxicity samples and 6,418 hepatotoxicity samples were collected for constructing the mitochondrial toxicity prediction model and M3Hep, respectively. To fully utilize the collected hepatotoxicity samples, this study developed a mitochondrial toxicity prediction model to predict mitochondrial toxicity for molecules without experimental mitochondrial toxicity data, achieving an AUC of 0.96 for the mitochondrial toxicity prediction model. The ablation study results of M3Hep indicate that incorporating mitochondrial toxicity enhances the performance of hepatotoxicity prediction models, further demonstrating the connection between mitochondrial toxicity and hepatotoxicity. M3Hep outperforms most baseline models across all metrics, with its AUC reaching up to 0.81. Moreover, in terms of the MCC metric, M3Hep surpasses all commonly used hepatotoxicity prediction tools collected, with a value of 0.49. In order to better understand the prediction mechanism of M3Hep, we conducted an interpretability analysis based on the GNNExplainer and SHAP methods.

Polysaccharides derived from marine algae are natural polymers with antioxidant, anti-inflammatory, and cytoprotectiveproperties, which make them promising for therapeutic use. In contrast, bromuconazole, a common triazole fungicide used in agriculture, has been associated with adverse effects such as oxidative stress, inflammation, and disruptions in cellular death pathways, raising safety concerns. This study investigates the potential of polysaccharides extracted from the red alga Osmundea pinnatifida (PSOP) to mitigate bromuconazole-induced toxicity. Through a subchronic 30-day exposure, 24 Wistar rats (6 per group) were divided into four groups: a control group, a bromuconazolegroup (32.8 mg/kg/day), a PSOP-only group (200 mg/kg/day), and a co-treatment group receiving both compounds. Bromuconazole exposure led to increased oxidative stress markers such as malondialdehyde (MDA), lipid hydroperoxides (LOOH), and advanced oxidation protein products (AOPP), along with decreased antioxidant defenses including glutathione peroxidase (GPx), reduced glutathione (GSH), non-protein thiols (NP-SH), and superoxide dismutase (SOD) in both liver and kidney tissues. These changes were accompanied by altered plasma biochemical parameters, indicating systemic toxicity. PSOP co-treatment alleviated oxidative stress by normalizing oxidation markers and enhancing antioxidant enzyme activities and non-enzymatic antioxidant defenses. Histopathological analyses confirmed PSOP's role in reducing tissue damage in the liver and kidneys. The HET-CAM assay also demonstrated PSOP's anti-irritant properties and ability to protect the vascular membrane during bromuconazole exposure. These results identify PSOP as an affordable, antioxidant-rich agent with significant biomedical potential, capable of protecting against oxidative damage induced by bromoconazole or xenobiotic.

The decontamination of chemical warfare agents or compounds involved in chemical industry incidents poses a significant challenge to environmental protection and human health. These compounds are highly toxic and could be relatively resistant to conventional decontamination methods. In recent years, surfactants have emerged as a promising option, as they can enhance the solubility of organophosphorus compounds in aqueous solutions while promoting their degradation or adsorption onto surfaces. In this study, 35 compounds (surfactants based on quartenary ammonium salts) were tested using the model pesticide fenitrothion, with the compounds from the 43 C series (quaternary ammonium salts with two hydroxyl functional groups) showing the highest decontamination potential. The 43 C series compounds were further tested in vitro for the degradation of nerve agents sarin, soman, and VX, as well as the blistering agent sulfur mustard. The compounds labeled 43C14 and 43C16 (benzoxonia with the 14- and 16-carbon chains) exhibited the best potential. Due to the possible use in protective applications for military personnel, an in vivo acute skin irritation test on 43C14 and 43C16 was also conducted in rats. No skin pathology was observed after a 4-h application and during the subsequent 72-h observation period, suggesting its potential for practical use.

In vitro human cell models are the gold standard for toxicological screening of environmental pollutants, allowing precise profiling of cellular responses. Pollutants with limited water solubility require carrier vehicles for uniform exposure. Ethanol, a commonly used vehicle, is typically maintained at 0.05-1.0% (v/v) to minimize toxicity. However, definitive no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs) for ethanol in non-tumorigenic human bronchial epithelial (BEAS-2B) cells, prevalent in inhalation studies, have not been established. Researchers thus apply a range of ethanol concentrations derived from diverse cell lines, increasing the risk of vehicle interference. This study evaluated ethanol as a cosolvent vehicle for four emerging high-flashpoint hydrocarbon (HFHC) dry cleaning solvents in BEAS-2B cells. HFHC solvents were solubilized 1:1 in 100% ethanol, then diluted in bronchial epithelial cell growth basal medium to final concentrations of 0.05%, 0.25%, 0.5%, and 2.5% (v/v). Vehicle, positive, and negative controls isolated ethanol-specific cytotoxic effects. Cytotoxicity was assessed via cellular viability (MTS assay) at 24 and 48 h, and lactate dehydrogenase (LDH) and interleukin-8 (IL-8) release after 24 h. Ethanol drove viability loss at ≥0.5% (24 h) and ≥0.25% (48 h), induced inflammation at concentrations ≥0.05%, and minimally impacted membrane integrity. Most HFHC solvents showed minimal effects beyond ethanol alone, except one HFHC, Intense, causing significant membrane disruption and cytotoxicity even at low doses (0.05-0.25%). Practical ethanol noninterference thresholds recommended are ≤0.5% for 24-hour assays, ≤0.25% for 48-hour viability, and ≤0.05% for inflammatory endpoints, establishing critical guidelines for ethanol use in BEAS-2B assays.

The widespread application of nanoparticles (NPs) has led to an increasing number of NPs being distributed in the ecological environment. This has raised concerns about human health and promoted the development of nanotoxicology. Traditional toxicity assessments, limited by high costs and time consumption, make machine learning (ML) an attractive alternative. ML models, particularly deep learning (DL) networks, can predict NP toxicity by analyzing extensive datasets, providing a more efficient and ethical method compared to animal testing. This review systematically summarizes the applications and challenges of ML in nanotoxicology. It discusses the importance of NPs properties in toxicity prediction and the difficulties in modeling the dynamic interactions with biological systems. The potential of integrating ML with other computational approaches to improve toxicity assessment is also considered. Despite progress, ML faces challenges such as limited training data, issues with model interpretability, and the complexity of nanomaterial-biological interactions. Overcoming these challenges requires enhanced data collection, interdisciplinary collaboration, and more directed ML models. Looking forward, the integration of ML with nanotoxicology is poised to revolutionize toxicity assessments, facilitating the development of safer nanotechnology applications.

Esophageal squamous cell carcinoma (ESCC), which has a high incidence and mortality rate in East Asia, arises from a complex interplay between genetic alterations and environmental exposures. Among environmental risk factors, endocrine-disrupting chemicals (EDCs) have attracted widespread attention, yet their impact on ESCC via gene interactions remains underexplored. This study integrated bioinformatics analysis to identify key genes and EDCs associated with ESCC pathogenesis. Chemical-gene interaction data were obtained from the Comparative Toxicogenomics Database(CTD), and differentially expressed genes(DEGs) were screened from the Gene Expression Omnibus (GEO) database. LASSO regression analysis prioritized five key genes (BUB1B, TPM2, KRT17, ADH1B, SALL4). Based on these genes, 25 EDCs potentially involved in ESCC were identified, of which 13 (such as benzo[a]pyrene) targeted at least three of the key genes. These findings suggested a novel EDC-gene-ESCC interaction network and provide insights into the environmental mechanisms underlying ESCC, offering potential targets for risk assessment and therapeutic intervention.

Background: Given the increasing therapeutic potential of cysteamine (CYST) at appropriate doses and expert concerns regarding the toxicity of nanoparticles, this study aimed to assess the toxicity profile of both CYST and silver nanoparticles conjugated with cysteamine (CYST-AgNPs).

Methods: For the acute study, a 300 mg/kg starting dose of CYST (i.p administration) produced a toxic response in some mice (n = 3/group), and a 300 mg/kg beginning dose of CYST-AgNPs produced delayed mild toxicity. Lower doses of CYST and CYST-AgNPs (50, 100, and 200 mg/kg; n = 3/group) were administered (i.p) for further acute toxicological evaluation. The sub-acute toxicity test was conducted for 21 days, and female mice (n = 5/group) were divided into control, CYST (25 and 50 mg/kg), and CYST-AgNPs (25 and 50 mg/kg). AgNPs and CYST-AgNPs were characterized with FTIR spectroscopy, UV spectrophotometer, HR-TEM, and SEM-EDX. Blood samples were collected via cardiac puncture and processed according to the standard hematological analysis protocols.

Results: The UV-vis absorbance wavelength range of 400-800 nm was observed. HR-TEM showed mostly spherical nanoparticles ranging from 30 to 90 nm. FTIR showed a functional group of O-H, C = C stretching vibration for AgNPs and O-H, S-H, N-H, C = C stretching vibration for CYST-AgNPs. EDX spectroscopy showed silver, carbon, oxygen, sodium, and chloride elements for AgNPs and CYST-AgNPs. The CYST decreased the WBC, RBC, and platelet counts significantly (p < 0.05), while CYST-AgNPs (25 and 50 mg/kg) reduced only the RBC counts (p < 0.05).

Conclusion: This investigation presents the in vivo safety analysis and pharmacological potential of cysteamine-modified silver nanoparticles (CYST-AgNPs), suggesting enhanced therapeutic activity.

This study aimed to evaluate the nephroprotective effect of Cilostazol on Cisplatin-induced nephrotoxicity. Female Wistar albino rats were divided into four groups: normal, Cis (8 mg/kg), and two Cilostazol treatment groups (30 and 60 mg/kg) with cisplatin. Cisplatin application significantly deteriorated renal function- manifested by increased serum creatinine (261%) and BUN (134%)-and enhanced oxidative stress-characterized by increased MDA (234%) and decreased GSH (64%). Cisplatin also affected autophagy markers, which included a 62% decrease in P62 and a doubling of LC3II. The PI3K/AKT/mTOR signaling pathway was significantly downregulated with reductions in PI3K (72%), mTOR (73%), and p-AKT/AKT ratio. NF-κB p65 was also increased by 1.5-fold. Moreover, an observed pronounced increase in the expression of TNF-α, caspase-3, and beclin-1 of the cisplatin-intoxicated rats. At the same time, Cilostazol (30 or 60 mg/kg) significantly reversed these changes, with a dose-dependent nephroprotective effect. At a higher dose (60 mg/kg), most parameters were comparable to the normal group, demonstrating superiority over the 30 mg/kg dose. These findings underpin that cilostazol modulates oxidative stress, inflammation, and autophagy pathways mainly via the PI3K/AKT/mTOR signaling axis to exert its renoprotective effect. Thus, cilostazol provides a promising potential in preventing cisplatin-induced nephrotoxicity. This outcome paves the way for the possible co-administration of cilostazol in the clinical realm to spare the deleterious effects of cisplatin.

Parkinson's disease (PD) is a progressive neurodegenerative disorder affects motor and cognitive functions in patients. The main pathology of this illness is the loss of dopaminergic neurons in the substantia nigra which leads to locomotor impairment such as tremors, bradykinesia, and muscular rigidity. In late stages of PD, non-motor symptoms like cognitive deficits develop, affecting the life quality. Recent studies indicated that these non-motor symptoms are attributed to neuronal loss in the hippocampus and impaired neurotransmission, due to oxidative stress and neuroinflammation. This study aimed to evaluate the antioxidant and anti-inflammatory effects of Taurine (TRN) and taurine nanoparticles (TRN-NPs) and investigate their role in improving hippocampal neuronal survival and their synergistic effects with Sinemet tablets as a dopamine replacement, on rotenone-induced PD experimental mice model. The experiment involved 70 mice categorized into G1:control, G2:Sinemet (reference drug), G3:TRN-control, G4:TRN-NPs-control, G5:Rotenone (PD model), G6: Rotenone + Sinemet, G7:Rotenone + TRN, G8:Rotenone + TRN-NPs, G9:Rotenone + Sinemet + TRN and G10:Rotenone + Sinemet + TRN-NPs. At the experiment end, Behavioral parameter was defined using inverted screen test and various assessments. Neurotransmitters, oxidative stress biomarkers, pro-inflammatory cytokines, brain-derived neurotrophic factor (BDNF), micro-RNA 214, and micro-RNA 216a were evaluated. Treatment with TRN or TRN-NPs alone or with Sinemet alleviate oxidative stress, neuroinflammation and hippocampal neurodegeneration, enhance neurotransmission, neuronal survival and protection against cellular death. These results were confirmed by histological and immunohistochemical studies. The results suggest that TRN-NPs represent an innovative adjunct supplement to traditional dopaminergic therapies, improve neuroprotection, increased bioavailability, addressing current limitations in drug delivery and therapeutic efficacy thus opening up promising therapeutic approaches for PD management.