Drug and Chemical Toxicology最新文献

N-nitrosodimethylamine (NDMA), as a disinfection by-product of drinking water, has been detected in various water. Epidemiological investigations have found that exposure to NDMA can exacerbate the development of diseases related to insulin resistance. In this study, male C57BL/6 mice were exposed to 0.5 and 12.5 mg/L NDMA by drinking water for 12 weeks. The mice in 12.5 mg/L NDMA group appeared fasting blood glucose elevation, and glucose tolerance and insulin sensitivity decreased. NDMA exposure enhanced hepatic gluconeogenesis and suppressed glycolysis of mice, but not affecting glycogen synthesis. In addition, NDMA exposure inhibited the phosphorylation of AMPK and FoxO1 as well as GLUT2 protein expression, and increased PGC-1α protein levels. GLUT2 protein decreasing could reduce glucose uptake of hepatocyte and enhance blood glucose concentration. Dephosphorylated FoxO1 might translocate to the nucleus, binding promoters of gluconeogenesis key enzymes PEPCK and G6Pase to upregulate their expression and promote gluconeogenesis. PGC-1α could also stimulate the expression of PEPCK and G6Pase. Furthermore, human normal liver cells (MIHA) were treated with NDMA for 24 hours. AMPK as a central energy sensor, regulates hepatic glucose production, uptake, and the process of glycolmetabolism. Therefore, AMPK agonist AICAR was used to explore the mechanism of NDMA causing hyperglycemia. AICAR reversed p-FoxO1, PGC-1α, GLUT2, PEPCK and G6Pase proteins expression and improved the glycolysis and glucose uptake capacity in NDMA treated MIHA cells. In conclusion, NDMA in drinking water led to fasting blood glucose enhancing, impairment of glucose tolerance and insulin sensitivity, increasing hepatic gluconeogenesis via AMPK signaling.

Alzheimer's disease (AD) is a common and debilitating neurodegenerative disease characterized by progressive cognitive impairment, and oxidative stress is a recognized contributor. Despite numerous studies, effective treatments remain scarce. This study synthesized and assessed the neuroprotective effects of a Schiff base complex, Copper(II) 4-(benzylideneamino)-3-hydroxynaphthalene-1-sulfonic acid [Cu(BAHN)₂], against scopolamine-induced (SCOP) cognitive and synaptic deficits in adult albino mice. Eight-week-old male BALB/c mice were randomly split into 4 groups: (1) controls (normal saline, 0.9%), (2) SCOP (1 mg/kg), (3) SCOP and Schiff base complex (30 mg/kg) and (4) Schiff base complex alone (30 mg/kg). Cognitive function was assessed using the Morris Water Maze (MWM) and Y-maze test. To assess the biochemical effects of the complex, antioxidant enzyme activities, and western blot analyses were performed. Treatment with the Schiff base complex significantly restored the activity of important antioxidant enzymes-catalase (CAT), peroxidase (POD), superoxide dismutase (SOD) and reduced glutathione (GSH) which were decreased by SCOP exposure. In addition, lipid peroxidation (LPO) rates were decreased. The complex also counteracted SCOP-induced decreases in both pre- and post-synaptic proteins, in line with improved behavioral performance in both cognitive challenges. Mechanistically, the compound activated phosphorylated Akt (p-Akt) and upregulated Nrf2 signaling, as well as downregulating nuclear factor kappa B (NF-kB) and interleukin-1β (IL-1β), show a decrease in neuroinflammation. In summary, these data suggest that the Schiff base complex reduces the oxidative, inflammatory, and synaptic deleterious effects of SCOP, probably, by regulating the p-Akt/Nrf2 pathway. Additional mechanistic studies are needed to understand its potential therapeutic implications in dementia.

Propolis or bee glue is a resinous mixture with several biological properties, which is collected by honey bees from flowers and plants sap. The current study was carried out to ascertain whether propolis provides defence against thioacetamide induced hepatic fibrosis. Wistar rats were randomly assigned into six groups having six animals in every group. Thioacetamide (200 mg/kg) was administered orally three times per week, whereas propolis at three different doses (100, 150 and 200 mg/kg) was administered three times per week alternatively to thioacetamide for continuous eight weeks. Hematology, serology, tissue biochemistry, and histology were carried out to assess thioacetamide induced fibrosis and hepatic injury as well as recovery pattern due to propolis. Five major compounds present in propolis were subjected to molecular docking analysis. Propolis decreased serological activity of AST, ALT, ALP, γ-GT, cholesterol, HDL, TG, bilirubin, triglycerides and increased level of albumin, glucose, and LDL. Propolis protected tissues from oxidative stress induced by thioacetamide in terms of LPO. Hydroxyproline, a marker of liver fibrosis was restored by propolis treatment toward control. Level of SOD, catalase, GSH, GR, GPx, GST, G6PDH in liver were upshifted in propolis treated groups. Molecular docking analysis interpreted interaction of phytochemicals present in propolis in ameliorating effects and role in preventing liver fibrosis. In vivo and in silico analysis concluded that propolis has hepatoprotective activity by reducing thioacetamide induced liver fibrosis in rats.

Introduction: Abrus precatorius (rosary pea) contains abrin, a highly potent ribosome-inhibiting toxin. Its seeds are well-known to be toxic when chewed or crushed, while boiled seed decoctions are occasionally used in traditional medicine.

Case report: We report a case of a 42-year-old male who developed gastrointestinal symptoms after ingesting decoction of 500 ml boiled water containing 50 g of Abrus precatorius seeds as a folk remedy. Despite the significant seed quantity, only the boiled water was consumed, not the seeds themselves. The patient presented with persistent vomiting and abdominal pain but remained hemodynamically stable and had normal laboratory findings. He was successfully managed with supportive care and discharged after 24 hours with no complications.

Conclusion: This case highlights that ingestion of Abrus precatorius decoction, without seed ingestion, may lead to mild toxicity. Awareness of such traditional practices is critical for early diagnosis and appropriate management.

Arctii Fructus is a frequently used Chinese materia medica and the dried ripe fruit of Arctium lappa L. (family Asteraceae). Previous studies discovered that the total lignans from Arctii Fructus (TLAF) could inhibit streptozotocin-induced diabetic retinopathy in addition to having hypoglycemic action on a variety of diabetic animal models. The oral toxicity of TLAF in rats has been reported, but there are no reports on its oral toxicity in beagle dogs. This study evaluated the acute and subacute toxicity of TLAF, as well as its effects on the respiratory and cardiovascular systems in beagle dogs at the first time. The approximate lethal dose of TLAF administered orally to beagle dogs was greater than 5000 mg/kg in the acute oral toxicity testing, and the respiratory and cardiovascular systems of conscious beagle dogs were not significantly affected by the oral administration of TLAF. However, repeated oral administration of TLAF (540 mg/kg) to beagle dogs for 28 days can cause 50% of administered animals to die. The toxic reactions are mainly seen in the digestive system, heart, liver, and kidneys. These results reduce the feasibility of developing TLAF as a clinical drug to treat diabetes and its complications.

Methiopropamine (MPA), a novel psychoactive substance (NPS) similar to methamphetamine (METH), warrants investigation into its neurotoxic effects on cognitive function and behaviors due to limited existing research. Therefore, this study aimed to explore the effects of MPA on several behavioral parameters in mice, brain levels of monoamine neurotransmitters, and p-ERK_1/2 expression. Mice were randomly divided into four groups (n = 10) which received daily intraperitoneal injections of either saline, 1 or 3 mg/kg of MPA, or 1 mg/kg of METH for 7 days. The novel object recognition test (NORT) revealed a significant decline in recognition memory, particularly evident at a dose of 3 mg/kg of MPA, similar to METH at 1 mg/kg, observed 24 h post-withdrawal. MPA at 3 mg/kg also impaired working and reference memory performance in the 8-arm radial maze (8-ARM) test and exhibited an anxiolytic effect in the open field test (OFT). These cognitive impairments were accompanied by decreased dopaminergic parameters and p-ERK_1/2 expression within the prefrontal cortex (PFC). This further suggests that MPA neurotoxicity is targeted at the dopaminergic transmission in the PFC. In conclusion, MPA consumption is associated with memory impairment, which is attributable to dopaminergic deficits and reduced p-ERK_1/2 activities in the PFC.

The herbicide atrazine (ATZ) has been implicated in metabolic disruptions. This study investigated the long-term consequences of pubertal ATZ-based herbicide exposure on the development of obesity in mice fed a high-fat diet (HFD) in adulthood. Male and female C57Bl/6 mice received ATZ (5 mg/kg) or water (control group) from postnatal day (PND) 30 to 60. Following puberty, all mice were fed a HFD for 90 days. Pubertal ATZ-based herbicide exposure increases food intake, specifically in male mice. While body weight, subcutaneous adiposity, and white adipose tissue (WAT) weights remained unchanged, ATZ-exposed male mice showed worsened adipocyte hypertrophy and upregulation of genes involved fat metabolism (Srebp-2, Ppar-γ, Cd36, and Adrp) in perigonadal WAT. Additionally, pubertal ATZ exposure exacerbated hepatic steatosis in both sexes, with increased ectopic fat accumulation in females correlating with increases in genes involved in fatty acid uptake and exportation (fatty acid transport protein 5 and microsomal triglyceride transfer protein). These findings provide new insights into the long-term metabolic consequences of pubertal exposure to ATZ, including exacerbated HFD-induced adiposity and hepatic steatosis. The observed sex-specific effects underscore the importance of considering pubertal windows of susceptibility to environmental disruptors and their potential impacts on adult health.

Deltamethrin, a synthetic pesticide, is toxic to both mammalian and nonmammalian animal species. Despite its widespread use in agriculture, food safety, and disease vector control, it poses a threat to a variety of organisms. The current study was designed to investigate the potential protective effects of chitosan, ivy leaf extract, or both on testicular toxicity when coadministered with the pesticide deltamethrin. Forty-eight rats were divided into eight groups of six each. All the animals were subjected to intragastric incubation for 90 days and received either saline (the control) or one of the following substances: the polysaccharide chitosan, ivy leaf extract, a combination of these two substances, deltamethrin alone, or a combination of deltamethrin with chitosan and ivy leaf extract. After the rats were euthanized, blood was drawn for biochemical assessment, and the testes were dissected for histological and immunohistochemical assessment. This study revealed that deltamethrin toxicity in rats resulted in reduced body weight, decreased sex hormones, increased oxidative activity, and decreased antioxidant defenses. Histopathological analysis revealed abnormal seminiferous tubules and damaged spermatogenic cells. The coadministration of chitosan and ivy leaf extract with deltamethrin reversed these effects by increasing body weight, reducing oxidative stress, and preventing histologic damage.

Mono-2-ethylhexyl phthalate (MEHP), a major metabolite of diethylhexyl phthalate, is increasingly recognized as an environmental contaminant with potential cardiovascular toxicity. However, the molecular mechanisms underlying MEHP-induced atherosclerosis (AS) remain poorly understood. This study aimed to investigate the toxicological targets and pathways through which MEHP contributes to AS development using network toxicology approaches. DEGs associated with AS were identified from the GSE100927 dataset. MEHP targets were predicted using multiple databases including SEA, SwissTargetPrediction, and TargetNet. Common toxicological targets were identified through intersection analysis. Functional enrichment analysis, GSVA, and ssGSEA were performed. Machine learning algorithms including LASSO regression, RF, and SVM were employed to identify key targets. A nomogram model was constructed for AS risk prediction, and molecular docking analysis was conducted to validate protein-ligand interactions. Analysis identified 13,905 DEGs in AS, with 172 potential MEHP targets yielding 92 common toxicological targets. Enrichment analysis revealed involvement in calcium signaling, PPAR signaling, inflammatory response, and immune pathways. Machine learning identified three key targets: PDPK1, HDAC10, and HRH1. The nomogram model based on HDAC10 and HRH1 demonstrated excellent predictive performance. ssGSEA analysis revealed significant associations between key targets and immune pathways. Molecular docking confirmed strong binding affinities, with HRH1-MEHP showing the highest affinity. MEHP may promote AS via coordinated effects on calcium handling, receptor-mediated and transcriptional signaling, oxidative stress, apoptosis, and immune activation. HRH1, HDAC10, and PDPK1 emerge as mechanistic mediators and potential biomarkers, with an HDAC10/HRH1 nomogram offering translational utility for AS risk stratification; docking results provide testable hypotheses for mechanistic validation.

Occupational exposure to diesel particulate matter (DPM) poses significant risks of pulmonary injury, highlighting an urgent need for effective pharmacological intervention. This study aimed to systematically elucidate the protective mechanism of aspirin against DPM-induced lung injury by integrating computational and experimental approaches. Methodologically, network pharmacology utilizing SwissTargetPrediction and GeneCards identified PTGS2 as the core therapeutic target via Venn diagram analysis and topological screening. Molecular docking and dynamics simulations then confirmed the stable binding of aspirin to the PTGS2 catalytic pocket. Biological validation was conducted via colony formation assay and Western blot in A549 cells, which demonstrated aspirin's efficacy in mitigating DPM-induced cytotoxicity and suppressing inflammatory and apoptotic pathways. Furthermore, in vivo studies incorporating HE staining and protein analysis in a mouse model corroborated the protective role of aspirin against DPM-induced alveolar damage and inflammatory infiltration. Collectively, our findings validate PTGS2 as a critical therapeutic target of aspirin against DPM-induced lung injury and highlight the promise of pulmonary-targeted aspirin formulations to enhance therapeutic precision while reducing systemic toxicity. Future efforts should focus on advancing the clinical translation of inhalable aspirin and validating its long-term efficacy in high-risk occupational populations.