Toxicology Research最新文献

This study explores the risk of Torsades de Pointes (TdP) arrhythmia, focusing on the interactions of parent drugs and their metabolites with the Human ether-à-go-go-related gene (hERG) channel, which is crucial in cardiac electrical activity and TdP risk assessment. Using a dual-strategy molecular docking approach with AutoDock Vina and PatchDock, we analyzed clinically relevant ligand pairs: astemizole/desmethylastemizole, terfenadine/fexofenadine, and quetiapine/norquetiapine. Quantitative analysis revealed that high binding affinity does not always correlate with toxicity. For instance, the non-cardiotoxic metabolite fexofenadine exhibited a higher binding affinity (-9.3 kcal/mol) compared to its toxic parent terfenadine (-8.9 kcal/mol), but its safety is explained by physicochemical constraints (zwitterionic nature). Conversely, desmethylastemizole maintained high affinity (-9.2 kcal/mol) with a geometrically "relaxed" fit (Atomic Contact Energy: -338.36), rationalizing its sustained potency. Geometric analysis further distinguished quetiapine as a "steric blocker" (Contact Area: ~588 Å²) causing forced occlusion, whereas its metabolite norquetiapine acted as a specific ligand with a significantly smaller interface area (~417 Å²). These findings highlight the importance of focusing not only on the parent drug but also on metabolites for TdP risk assessment in new drug development. We advocate for an integrated computational framework combining binding energy, geometric complementarity, and physicochemical profiling to enhance the accuracy of early cardiac safety screenings.

As a predominant contributor to end-stage renal disease, diabetic nephropathy (DN) progression is critically influenced by podocyte impairment, which serves as a pivotal determinant in the initiation of proteinuria and subsequent renal functional decline. MicroRNAs (miRNAs) act as key post-transcriptional regulators that modulate target gene expression through mRNA degradation and/or translational repression. Previous studies have demonstrated that the upregulation of human runt-associated transcription factor 3 (RUNX3) suppresses the epithelial-to-mesenchymal transition (EMT) in renal tubular epithelial cells in DN. But, the role of RUNX3 in podocyte-specific EMT and its regulation by miRNAs has not been comprehensively explored. This study aimed to investigate whether the microRNA mmu-miR-664-5p contributes to high glucose (HG)-induced podocyte injury by targeting RUNX3 and to determine if Shenxiao decoction (SXD) exerts its protective effect through this pathway. We found that HG significantly upregulates mmu-miR-664-5p, which directly binds to the 3' UTR of RUNX3 mRNA. Inhibition of mmu-miR-664-5p in HG-induced mouse podocyte clone-5 (MCP5) enhanced cell viability, reduced apoptosis, migration, and invasion, and reversed EMT marker expression. We further discovered that SXD-containing serum (SCS), counteracts HG-induced podocyte EMT by downregulating mmu-miR-664-5p and restoring RUNX3. Conversely, adding exogenous miR-664-5p mimetic to SCS-treated HG media reversed these protective effects. In conclusion, mmu-miR-664-5p promoted the EMT effect of MPC5 podocytes in HG medium by targeting RUNX3, and SXD mitigates this process through its inhibition of miR-664-5p, collectively highlighting the mmu-miR-664-5p/RUNX3 axis as a prospective target for therapeutic intervention in DN.

This study investigated the preparation of PLGA nanoparticles loaded with Quercetin (Que), 4-octyl Itaconate (4-OI), and Pirfenidone (PFD) utilizing a microfluidic method. The therapeutic efficacy of a combination of these nanoparticles was evaluated to assess their potential in overcoming Paraquat (PQ)-mediated cytotoxicity in human embryonic lung fibroblasts (MRC-5) cells. The characterization of synthesized nanoparticles was conducted, foucusing on parameters such as size, zeta potential, transmission electron microscopy (TEM), encapsulation efficiency, and in vitro profiles of drug release. The cytotoxicity and protective activity of the combination therapy were evaluated through MTT tests. The characterization results revealed high Entrapment efficacy (≈ 65%), proper particle sizes (166-173 nm), narrow polydispersity index (PDI) (0.236 ± 0.06 to 0.289 ± 0.07), and significant stability over 30 days. The optimum concentrations of PQ (IC50 = 103 ± 4.54 μM) and combination therapy (Que 25 μM, 4-OI 25 μM, and PFD 400 μM) and PLGA combination therapy (PLGA-Que 2.5 μM, PLGA 4-OI 5 μM, and PLGA-PFD 50 μM) were evaluated. Oxidative damage was assessed, by measuring reactive oxygen species (ROS), lipid peroxidation (LPO), Protein carbonyl (PC), and glutathione content (GSH). Results revealed that combination therapy significantly increased cell viability compared with the single administration of PQ alone. PLGA combination therapy was more effective at low doses compared with the same free drugs in terms of cell viability. Oxidative biomarkers significantly decreased, while GSH levels significantly increased in PLGA combination therapy compared to the traditional triple combination therapy. These observations confirm that the synergistic activity of Que, 4-OI, and PFD delivered through PLGA nanoparticles exhibits substantial therapeutic potential for controlling paraquat poisoning and its pulmonary complications.

Propofol, a widely used intravenous anesthetic, has raised concerns regarding its potential neurotoxic effects on the developing brain. This study aimed to investigate the specific molecular mechanisms underlying propofol-induced neuronal damage during early development. Postnatal day 7 C57BL/6 J mice received a single intraperitoneal injection of propofol (50, 100, or 200 mg/kg) and hippocampal tissues were harvested 12 h post-exposure. Primary hippocampal neuronal cultures from mice embryos were exposed to propofol for 24 h. Genetic manipulations, including EGR4 and NPAS4 overexpression via plasmid transfection (in vitro) and adenovirus injection (in vivo), as well as NPAS4 knockdown using siRNA, were employed. Assessments included histopathology, apoptosis, cell viability, gene/protein expression, and transcriptional regulation. Propofol administration induced dose-dependent hippocampal neuronal injury in neonatal mice. Both in vitro (primary neurons) and in vivo (hippocampal tissue), ectopic overexpression of EGR4 via genetic manipulation significantly attenuated propofol-induced neurotoxicity. Mechanistically, EGR4 was found to directly bind to the NPAS4 promoter and positively regulate its transcription. Crucially, the anti-apoptotic effect of EGR4 overexpression was abolished upon NPAS4 knockdown. Our findings reveal a novel EGR4/NPAS4 transcriptional cascade through which propofol exerts its neurotoxic effects in the developing brain. Propofol downregulates EGR4 expression, leading to reduced NPAS4 transcription and subsequent neuronal apoptosis. While this pathway represents one potential mechanism of propofol-induced developmental neurotoxicity, it identifies EGR4 and NPAS4 as potential targets for therapeutic strategies aimed at mitigating anesthetic-related neuronal injury in the vulnerable developing brain.

The global increase in sucrose consumption due to higher living standards poses a public health challenge, as it is linked to metabolic disorders such as obesity and cardiovascular diseases. D-psicose, a natural monosaccharide and fructose epimer, is a low-calorie sweetener alternative with 70% of sucrose's sweetness. This meta-analysis used male rat models to study D-psicose's effects on body weight and lipid profiles. After searching eight databases, seven studies were selected and assessed using SYRCLE's tool. Results showed that D-psicose significantly reduced body weight gain in male rats (MD: -2.31 g, 95% CI: -3.12 to -1.50), especially in Wistar strains. However, lipid parameters such as TG and TC did not change significantly. There were trends of improved lipoprotein profiles (lower LDL-C, higher HDL-C), but these were not statistically significant. Despite the limited number of studies, D-psicose may regulate body weight without markedly affecting lipid metabolism in rodents. More well-controlled preclinical studies with standardized protocols are needed to better understand its effects and potential human applications.

Parkinson's disease (PD) is a progressive disorder that affects its patients' life quality due to the loss of dopaminergic (DAergic) neurons of substantia nigra (SN), and development of Lewy bodies (LBs) mediated by accumulation of alpha-synuclein (α-Syn) in the brain, causing progressive neuronal loss, and locomotor impairments such as tremor, rigidity, and postural instability. Various pathological factors impact PD progression, such as oxidative stress, neuroinflammation, and kinase activity alterations. This study aimed to evaluate the neuroprotective impacts of Taurine and Taurine nanoparticles (TRN-NPs) alone or along with Sinemet® tablets (ST), investigating their role in attenuating striatal neurodegeneration induced by Rotenone (ROT), a pesticide used to replicate PD-like phenotypes. The study animals were 70 mice, categorized into 10 groups: G1: Normal control, G2: ST control, G3: Taurine control, G4: TRN-NPs control, G5: ROT-induced PD, G6: ROT+ST, G7: ROT+Taurine, G8: ROT+TRN-NPs, G9: ROT+ST + Taurine, and G10: ROT+ST + TRN-NPs. Evaluation of motor function, analysis of brain oxidative stress, pro-inflammatory mediators, and phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2) activity, along with assessment of gene expression of tyrosine hydroxylase (TH) and synuclein alpha interacting protein (SNCAIP), were performed. The obtained results showed that both Taurine and TRN-NPs improved antioxidant activity, alleviated neuroinflammation, modulated p-ERK1/2 levels, and exhibited marked neuroprotective characteristics observed via histopathological examination of striatum tissue; these effects were more promising in combined treatment groups, which illustrates that the co-administration of TRN-NPs with ST yields a more effective synergistic impact in alleviating ROT-induced Parkinsonian pathologies than monotherapies, indicating a potential viable combinatorial approach for PD management.

This study assesses the impact of the COVID-19 pandemic on enquiry numbers to the United Kingdom (UK) National Poisons Information Service (NPIS) to inform public health interventions. Phone enquiries were extracted and analysed from the UK Poisons Information Database (UKPID) in calendar years 2018 to 2020. Data collected included information on call, patient, and exposure characteristics for all enquiries and for specific enquiries involving selected agents of interest. During the first national lockdown there was a significant decrease in the proportion of enquiries about intentional exposures (20.6%) compared to pre lockdown (26%) and control periods (22.6%) (P < 0.001), potentially due to reluctance to attend healthcare facilities. Exposures regarding dental analgesics also increased significantly in lockdown (5.15%) compared to pre-lockdown (2.6%) and the control period (3.4%) (P < 0.001) likely due to limited access to dental services. Enquiries about hand sanitisers exposures showed a significant increase during lockdown (92) compared to pre-lockdown (32) and control (45) (P < 0.001) likely due to increased availability. No significant increases in exposures were identified for selected pharmaceuticals of interest and only a small number of enquiries relating to exposures with essential oils, methanol, Chinese herbal medicines antihistamines and deliberate bleach ingestion which offered reassurance from a public health perspective. This data led to public health interventions such as tweets, updates to guidance and advice to healthcare professionals and the public. Toxicovigilance is a key public health tool and poison centre enquiry data is helpful in identifying toxic exposures for any future pandemics or large-scale chemical incident.

Copper oxide nanoparticles (CuONPs) are widely used in gas sensors, high- temperature conductors, and as antimicrobial agents, yet concerns remain regarding their potential toxicity. Silybum marianum (SM), or milk thistle, is known for its hepatoprotective and antioxidant properties. This study aimed to assess the genetic and pathogenic effects of CuONPs on adult male Wistar albino rats and to evaluate the protective role of milk thistle. Thirty-two male Wistar rats were divided into four groups (n = 8): Group 1 (control), Group 2 (SM) received oral milk thistle (50 mg/kg/day) for 4 weeks, Group 3 (CuONPs) was intraperitoneally injected with CuONPs (50 mg/kg/day) for 3 weeks starting from day 7, and Group 4 (SM + CuONPs) received SM alone for one week then both SM and CuONPs for the next 3 weeks. Blood, bone marrow, liver, and kidney samples were collected for molecular, histopathological, immunohistochemical, and biochemical analyses. Group 3 showed DNA damage, reduced mitosis, and degeneration in liver and kidney tissues, along with increased expression of PCNA, Bax, and Cyclin D and elevated enzyme levels. In contrast, Group 4 (SM + CuONPs) exhibited notable improvement, with preserved tissue structure, reduced oxidative damage, and normalized enzymes. In conclusion, CuONPs induced genetic and organ toxicity, while S. marianum demonstrated a protective effect against these adverse outcomes.

A previous study demonstrated that Nrf2, a transcription factor, unexpectedly promoted multi-walled carbon nanotube (MWCNT)-induced lung inflammation in mice. This finding contrasts with the well-established role of Nrf2 in suppressing inflammatory responses induced by environmental chemicals, highlighting a critical knowledge gap. The present study investigated the effect of sulforaphane, a known activator of Nrf2, on MWCNT-induced lung inflammation in mice, in order to better understand the underlying mechanisms of this response. Each of 48 C57BL/6 J male mouse was anesthetized and exposed once via pharyngeal aspiration to MWCNTs (Mitsui-7) at doses of 0, 10, or 20 μg in 40 μl of dispersion medium per mouse and treated thereafter with subcutaneous 25 mg/kg/day sulforaphane or vehicle for 14 days. Bronchoalveolar lavage fluid (BALF) was collected for differential cell counts. Lung tissues were processed for histopathological analysis and quantification of cytokine or chemokine mRNA expression and Nrf2 protein in nuclear extracts. MWCNTs exposure increased lung weight, BALF lymphocytes, and lung IL-6 expression. Sulforaphane attenuated MWCNTs-induced lung weight gain, lymphocytic infiltration, and upregulation of IL-6 expression, but paradoxically enhanced low-dose MWCNT-induced neutrophil infiltration in BALF, MIP-2 expression, and histopathological inflammation scores. These effects were accompanied by increased levels of active Nrf2 protein in nuclear extracts from lung tissue. Overall, the results indicate that sulforaphane suppresses lymphocyte infiltration while promoting neutrophil recruitment in response to low-dose MWCNTs, suggesting a dual effect of sulforaphane on MWCNT-induced lung inflammation mediated through Nrf2 activation.

Hypoxia, during early embryonic development, causes morphological and functional impairments through oxidative stress. Melatonin, a strong antioxidant, may exert potential protective effects in this process. This study investigated the effects of melatonin on yolk sac vascularization and embryonic development in rat embryos exposed to hypoxia. Rat embryos at gestational day 9.5 were cultured for 48 h using a whole embryo culture (WEC) system. Embryos were divided into six groups: Control (C), Hypoxia (H), 10 μM Melatonin (10 μM Mel), Hypoxia +10 μM Melatonin (H + 10 μM Mel), 50 μM Melatonin (50 μM Mel), and Hypoxia +50 μM Melatonin (H + 50 μM Mel). At the end of culture, morphological parameters, oxidative stress markers, and the distribution of vWF-positive cells were evaluated. Compared with the control group, the H group exhibited marked developmental delay and vascularization defects (P < 0.05). Melatonin administration significantly reduced these abnormalities, with the 50 μM melatonin group showing the most prominent improvements in morphological development, oxidative stress parameters, and vascularization (P < 0.05). Melatonin provides protective effects against hypoxia-induced early embryonic developmental impairments and holds therapeutic potential as an agent supporting development during the early intrauterine period.