Toxicology Research最新文献

Chronic low-level exposure to nickel (Ni), copper (Cu), and arsenic (As) may contribute to myocardial injury via oxidative stress. This study investigated the effects of these metals in male Sprague-Dawley rats exposed to aerosols of Ni (0.106 mg/m³), Cu (0.048 mg/m³), and As (0.025 mg/m³) at environmental and 10-fold concentrations for 3 mo. Blood metal levels were analyzed using inductively coupled plasma-mass spectrometry (ICP-MS), and oxidative stress and myocardial injury biomarkers were measured with enzyme-linked immunosorbent assay (ELISA). Blood As levels showed a dose-dependent increase in both exposure groups. Myocardial ultrastructural damage, including mitochondrial swelling, disorganized myofibrils, and increased autolysosomes, was observed. Biomarkers of oxidative stress, including catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH), were significantly elevated in both exposure groups, while malondialdehyde (MDA) levels were notably higher in the 10-fold group. Myocardial injury markers (TNNI3, LDHA, and α-HBDH) were elevated in both exposure groups. Significant correlations were found between Cu and As levels and oxidative stress and myocardial injury biomarkers. These findings demonstrate that prolonged low-level exposure to Ni, Cu, and As induces oxidative stress and myocardial injury in rats. The results highlight the potential cardiovascular risks associated with environmental exposure to mixed heavy metals and emphasize the importance of stricter regulatory measures to limit such pollutants.

The term ``anabolic-androgenic steroids'' (AASs) refers to a class of artificial substances that resemble the natural testosterone. The most often misused androgen, nandrolone decanoate (ND), is regarded as a public health concern that needs immediate action to raise public awareness of toxicology results on AAS usage. This study designed to investigate the therapeutics effect of nano ferrite-chitosan-curcumin nanoparticles (NF-CH-CurNPs) against ND induced renal toxicity, proliferation, inflammation, and oxidative stress in male rats. A total of 48 adult male rats were assigned randomly to 6 groups [1^st group was control; 2^nd group was CurNPs where rats received CurNPs (50 mg/kg BW/2 day) for two wk; 3^rd group was NF-CH-CurNPs where rats received NF-CH-CurNPs (24 mg/Kg BW/2 day) for 2 wk.; 4^th group was ND where rats received ND (25 mg/Kg BW/wk) for four wk; 5th group was ND + CurNPs in which rats received ND for 4 wk then treated with CurNPs for another 2 wk; 6^th group was ND + NF-CH-CurNPs where rats received ND for 4 wk then treated with NF-CH-CurNPs for another 2 wk]. A significant elevation in serum Urea, creatinine, kidney damage, MDA, PCNA, TNFα and a significant depletion in sodium, potassium ions, catalase, SOD, GSH after ND administration as compared to control. On the contrary, treatment of ND with CurNPs or/and NF-CH-CurNPs induced significant enhancements of the studied parameters, kidney structure and functions, oxidative stress, PCNA and TNFα expressions with best results for the treatments with NF-CH-CurNPs that may possibly scavenge free radicals creating valuable effects in contrast to ND.

Manganese (Mn), a vital trace element for biological functions, has raised health concerns due to potential toxicity. Excessive Mn impairs male reproduction by reducing testosterone, inducing oxidative stress, and disrupting spermatogenesis. However, its mechanisms targeting Leydig and Sertoli cells remain unclear. This study investigates Mn's reproductive toxicity by utilizing Leydig cell line TM3 and Sertoli cell line TM4, MTT assays revealed median lethal concentrations of 230 μM (TM3) and 170 μM (TM4), with AO/EB/DAPI staining confirming condensed nuclei and enhanced fluorescence. Apoptosis inhibitor Z-VAD-FMK (20 μM) suppressed cell death in both cell lines, whereas ferroptosis inhibitor Ferrostatin-1 (10 μM) specifically attenuated TM4 cell death. Necrosis inhibitor Necrostatin-1 (10 μM) showed no protective effect. Mn triggered ROS elevation in TM4 cells, accompanied by upregulated Caspase 3, Casp8ap2, GPX4, Gtf3c1, Mtfr1, HMOX1, and SLC7A2, while downregulating SLC7A15. These findings reveal Mn activates apoptosis in TM3 cells and concurrent apoptosis/ferroptosis in TM4 cells through ROS-dependent dysregulation of apoptosis- and ferroptosis-related genes. These findings establish distinct toxic mechanisms in TM4 cells and highlight the SLC7A15/HMOX1 axis as a therapeutic target to mitigate Mn-induced spermatogenic damage.

Acute poisoning typically accounts for 1%-3% of all emergency department (ED) visits, and comprise 4%-40% of admissions to intensive care units (ICU), with a mortality rate of 3%-6%. Accurate assessment of patient prognosis enables the early implementation of appropriate interventions and the effective allocation of limited resources, thereby preventing adverse outcomes. However, it remains unclear which tool offers superior predictive accuracy for the prognosis of poisoned patients. In this article, we review existing assessment tools used to predict mortality risk in poisoned patients and compare their performance. We conducted comprehensive searches in PubMed, EMBASE, Ovid, Scopus, Cochrane Library, CNKI, Wanfang Data, and SinoMed databases from their inception up to January 2025. Studies were included if they reported the performance of at least one scoring systems for predicting mortality in patients with acute poisoning. The PRISMA guidelines were followed (PROSPERO registration: CRD42024579941). Data of 60,403 patients across 65 studies were eligible for inclusion. The risk assessment tools reported in more than three studies included APACHE II (47), SOFA (19), SAPS II (11), PSS (16), MEWS (8), REMS (5), new-PMS (5). Significant heterogeneity was observed in the pooled analysis. In this study, PSS exhibited moderate sensitivity and specificity in predicting mortality among patients with acute poisoning, while MEWS demonstrated the highest sensitivity, and new-PMS showed the strongest specificity. The highest AUC values were observed for MEWS and APACHE II. Based on these findings, MEWS and new-PMS may represent the optimal tools for predicting in-hospital/28-day/30-day mortality in poisoned patients.

Per- and polyfluoroalkyl substances (PFAS) are emerging environmental contaminants linked to various health conditions. However, the molecular mechanisms by which PFAS contribute to OA remain unclear. This study integrates network toxicology and bioinformatics to explore PFAS-related toxicity targets and their roles in OA pathogenesis. Transcriptomic data from the GSE48556 dataset were analyzed to identify differentially expressed genes (DEGs). PFAS-related genes (PSRGs) were retrieved from the CTD. Cross-analysis revealed overlapping genes, which were further evaluated via protein-protein interaction (PPI) networks, pathway enrichment, immune infiltration analysis, and nomogram construction. A total of 1,703 DEGs (910 upregulated, 793 downregulated) were identified in OA. Cross-analysis with 346 PSRGs yielded 26 overlapping genes, highlighting PFAS-OA molecular links. Enrichment analysis implicated IL-17 signaling, Th1/Th2 differentiation, and fatty acid metabolism as key pathways disrupted by PFAS. Immune-inflammatory pathways were robustly enriched, with CD3E, CARD11, and IFNG driving synovial inflammation. A nomogram incorporating five core targets (CARD11, IFNG, PAX8, PLD1, ZNF609) predicted OA risk and demonstrated clinical utility via decision curve analysis. Immune profiling revealed elevated infiltration of T cells, Th1 cells, and NK CD56dim cells in OA, alongside upregulated antigen presentation and TCR/BCR signaling. Core PFAS-related targets correlated significantly with immune dysregulation. PFAS exposure exacerbates OA by dysregulating immune-inflammatory axes and metabolic pathways, promoting synovitis and cartilage degradation. The identified genetic targets and nomogram provide mechanistic insights and translational tools for OA risk prediction in PFAS-exposed populations. This study establishes a systems-level framework linking PFAS toxicity to OA progression, offering actionable targets for therapeutic intervention.

This study aimed at exploring the expression characteristics and functional roles of PTTG1 in ccRCC by bioinformatics analysis and in-vitro experiments. Differentially expressed genes were screened based on TCGA-KIRC and GSE168845 and the protein-protein interaction network was constructed. The risk regression model was constructed by Lasso regression and the key prognostic genes were obtained by combining immune infiltration and pathway enrichment analysis. Genes and proteins were quantified using RT-qPCR and western blot. MTT assay was used to detect the vitality of cells. Cell apoptosis and cell cycle were detected by flow cytometry. The comet assay was adopted to detect the damage degree of cell DNA. Six significant DDR-relevant prognostic genes (CCNA2, CDC45, CTLA4, FOXM1, PLK1, and PTTG1) were obtained. Immune infiltration results showed that CTLA4 was significantly positively correlated to T cells CD8. Besides, PTTG1 was negatively correlated to T cells CD4 memory resting, but remarkably positively correlated with both T cells CD8 and T cells regulatory. Compared with normal renal proximal tubular epithelial cells, the protein expression of PTTG1 was up-regulated at both mRNA and protein levels in ccRCC tissues. PTTG1could notably promote the proliferation of 786-O cells, and significantly inhibited apoptosis, cycle arrest and DNA damage of 786-O cells. PTTG1 may play a carcinogenic role by promoting the proliferation of ccRCC cells and inhibiting apoptosis. PTTG1 is expected to become a potential diagnostic and prognostic biomarker as well as an immunotherapy target for ccRCC.

The main objective of this research was to investigate the therapeutic, anti-inflammatory, and histological effects of metformin and taurine, both alone and in combination, against thioacetamide (TAA)-induced hepatotoxicity in rats. The study included forty adult male Swiss albino rats, which were divided into five groups: Group I provided the control group. Group II (TAA group) rats received injections of TAA (200 mg/kg b.wt /3 times/week, i.p.) for six weeks. Group III (TAA + metformin) rats received administration of metformin (200 mg/kg/day, p.o.) for five weeks. Group IV (TAA + taurine) rats received injections of taurine (100 mg/kg/day, i.p.) for five weeks, while Group V (TAA + metformin + taurine) rats received daily intraperitoneal injections and oral administration of the medication for five weeks. Inflammation and changes in liver function are hallmarks of TAA-induced hepatotoxicity. Our findings demonstrated that the greatly improved liver dysfunction might be attributed to the effects of metformin and taurine. Furthermore, a combination of metformin and taurine markedly inhibited inflammatory responses, as indicated by the decreased levels of the inflammatory cytokine IL-6. The biochemical results were confirmed by the histological analyses of the liver tissues. Post-treatments of metformin and taurine might have crucial potential and synergistic effects against TAA-induced hepatotoxicity.

Liver injuries, especially those induced by chemical toxins and pharmaceuticals, are increasingly prevalent. This study evaluated the hepatoprotective effects of Ginkgo biloba and dandelion extracts in a rat model of thioacetamide (TAA)-induced liver injury. Twenty-eight male albino rats were randomly assigned to four groups: control, TAA-treated, TAA plus G. biloba (100 mg/kg), and TAA plus dandelion (500 mg/kg). TAA administration over eight weeks significantly elevated serum liver enzymes (AST, ALT, ALP, and GGT), bilirubin, cholesterol, and triglycerides (P < 0.05) while significantly reducing total protein and albumin levels (P < 0.05). TAA also induced oxidative stress, evident by increased hepatic malondialdehyde and reduced glutathione levels (P < 0.05). Co-treatment with G. biloba or dandelion extracts significantly ameliorated these biochemical alterations (P < 0.05), with G. biloba demonstrating slightly stronger effects. Histopathological examination showed reduced necrosis, fibrosis, and inflammatory cell infiltration in treated groups. Immunohistochemical analysis confirmed decreased expression of TNF-α and P53 proteins (P < 0.05), indicating anti-inflammatory and anti-apoptotic properties. These findings suggest that G. biloba and dandelion extracts confer protective effects against TAA-induced liver damage through antioxidant, anti-inflammatory, and anti-apoptotic mechanisms.

Interest in inhibiting target proteins through covalent binding mechanisms has increased in the last decade due to the potential for beneficial pharmacological properties. However, the inherent targeted covalent inhibitor (TCI) adverse off-target reactivity risk requires a mitigation strategy early during drug discovery. The aim of this research was to design a pre-clinical hepatic safety assessment strategy for TCIs considering risk associated with electrophilic warhead reactivity and reactive metabolites formation at clinically-relevant plasma concentrations. The mitigation strategy was applied to compound 35, a potent irreversible inhibitor to KRAS^G12C. Drug induced liver injury was assessed in primary human hepatocyte spheroids. GSH and ATP depletion were investigated for compound 35 and 6 other marketed TCIs containing an acrylamide warhead which binds irreversibly to cysteine-containing target proteins. None of the TCIs showed GSH depletion prior to ATP depletion after 7-days exposure, suggesting that GSH depletion was not driving cytotoxicity in the spheroids. The calculated hepatotoxicity margin towards plasma exposure of 2.5 for compound 35 was found to be in the same range as for the two KRAS^G12Cinhibitors adagrasib and sotorasib, with clinically reported treatment-related adverse aminotransferase elevations leading to dose modifications. The safety evaluation reported here suggests no negative discrepancy in liver toxicity for compound 35 versus similar approved TCI's. Finally, the risk associated with detected oxidative metabolites was further mitigated as the pan-CYP450 inhibitor 1-aminobenzotriazole (ABT) had no effect on the cytotoxicity response following incubation of compound 35 in the presence and absence of ABT.

In this study, the therapeutic synergistic effects of metformin (MET) and Apricot Kernel Oil (AKO) were investigated in an animal model of bisphenol A (BPA)-induced polycystic ovary syndrome (PCOS). BPA disrupts endocrine functions and induces oxidative stress in ovarian tissues, leading to PCOS. AKO and MET target underlying mechanisms associated with PCOS, particularly those related to insulin resistance and oxidative stress, which are critical in the pathology of this condition. Antioxidant activities, total phenolic, and flavonoid contents of AKO were performed. The AKO underwent liquid chromatographic-electrospray ionization tandem mass-spectrometric (LC-ESI-MS/MS) analysis after acetonitrile treatment. PCOS was induced in adult Wistar rats by administering BPA. After 60 days, the 70 rats were divided into seven groups (n = 10/group): Normal, PCOS, MET, AKO, and co-treatment with MET and AKO. On the 22^ndday of the study, serum catalase, glutathione peroxidase, superoxide dismutase activity, LH, FSH, progesterone, estrogen, and testosterone hormones alongside inflammatory cytokines (TNF-a, IL-6, CRP, and IL-1β) and nitric oxide levels were measured. Ovarian tissues were isolated for measurements of ferric reducing ability of plasma and thiobarbituric acid reactive substances levels. The expression of genes and proteins related to mitochondrial and PI3K/AKT pathways was analyzed. The results demonstrated that AKO, in synergy with MET, modulated hormone levels, reduced pro-inflammatory cytokines, and enhanced antioxidant properties. AKO, in combination with MET modulated apoptosis via mitochondrial and PI3K/AKT pathways. These findings suggest that AKO holds promise as a potential therapeutic option for women with ovulation disorders, particularly those affected by bisphenol A-induced PCOS.