Human & experimental toxicology最新文献

IntroductionHepatotoxicity can arise secondary to several medical conditions, including inflammation, sepsis, and therapy. Lipopolysaccharide (LPS) can activate diverse inflammatory pathways and has been implicated in hepatotoxicity. The store-operated calcium entry (SOCE), a key process for maintaining cellular calcium homeostasis, was shown to modulate inflammatory signaling. Reactive oxygen species, which serve a significant role in maintaining cellular function and homeostasis, are often elevated during inflammation, contributing to tissue injury. Therefore, we hypothesized that blocking the SOCE pathway would inhibit LPS-induced hepatotoxicity by suppressing inflammation and oxidative stress.MethodsTo test this, female BALB/c mice were randomly divided into the following experimental groups: control, LPS, LPS + SOCE inhibitor 2-aminoethoxy diphenyl borate (2APB), and 2APB alone. After 24 h of treatment, serum and liver samples were collected from the mice for histopathological, biochemical, and molecular analyses.ResultsInhibition of SOCE led to a decrease in the elevated liver function enzymes (ALT and AST) and protected the liver parenchymal cells as observed by histopathological assessment. Furthermore, blockade of SOCE significantly suppressed the level of il-1b, il-6, and cox2 genes in the liver tissues of mice treated with LPS. The expression of antioxidant genes (gsta1 and gpx1) was also significantly reduced by LPS treatment, while SOCE inhibition only restored the gpx1 expression. Additionally, treatment with 2APB attenuated LPS-induced oxidative stress in the liver of mice.ConclusionCollectively, our work demonstrated the critical involvement of SOCE in regulating inflammation and oxidative stress associated with LPS treatment, thereby reducing hepatotoxicity.

ObjectiveBronchopulmonary dysplasia (BPD), a common chronic lung disease in premature infants, is frequently complicated by pulmonary hypertension (PH), a dangerous condition characterized by elevated pulmonary vascular pressure. At present, the most classic and commonly used animal model for BPD involves exposure to high oxygen concentrations, but existing studies based on this model have seldom addressed whether it recapitulates the pathological features of PH.MethodsIn the present study, we established a rat model of BPD complicated with PH (BPD-PH). Histological hematoxylin and eosin (H&E) staining, enzyme-linked immunosorbent assay (ELISA), flowcytometry, reverse transcription-quantitative PCR (RT-qPCR), wound healing assay, transwell migration and invasion assays, transcriptome RNA-sequencing and GO analysis were performed to evaluate this BPD-PH model.ResultsOur study demonstrated that rats with BPD-PH exhibited characteristic alveolar simplification and features of pulmonary hypertension, including increased mRVP, RV/LV + S and RV/WT. BPD-PH rats had enhanced inflammatory response and increased accumulation of immune cells in lung. Moreover, differentially expressed genes in the BPD-PH rat model were depicted and we found Leucine-rich alpha-2-glycoprotein 1 (Lrg1) was significantly upregulated by 19.32 fold (p < 0.001). LRG1 affected migration, invasion and transforming growth factor-β (TGF-β) signaling activation in primary alveolar epithelial cells and pulmonary endothelial cells. Finally, our BPD-PH model was used for the evaluation of two commonly used drugs for BPD and PH, Dexamethasone and Sildenafil. These two drugs were effective in alleviating lung injury, inflammatory response and hypoxia-induced PH in the rat model of BPD-PH.ConclusionOur data indicate that we established a novel BPD-PH model in rats, and it provided a new choice for the future research for BPD complicated with PH.

IntroductionAging and metabolic disease enhance inhaled particulate toxicity. Nanoparticles (NPs) are rapidly coated with biomolecules forming a biocorona (BC), upon entering the body and may contribute to the susceptibility. Aging and metabolic syndrome (MetS) are progressive conditions resulting in biomolecule alterations over time potentially influencing susceptibility. We hypothesize NP-biomolecule interactions are altered during aging and throughout MetS progression.MethodsC57BL/6J mice at 6 weeks of age were fed a healthy diet or a high-fat western diet. BALF was collected after 2, 4, 8, 12, 16, 20 or 24 weeks on diets. NP-biomolecules interactions were compared between healthy and MetS to determine age- and disease progression-related BC variations (proteins and lipids).ResultsUnique BCs were determined to form at each time point indicative of aging for the healthy and aging and disease progression for the MetS. Comparisons between healthy and MetS BCs at each time demonstrated distinct biomolecule interactions attributable to disease. Comparisons determined both unique protein and lipid content as well as quantitative differences. Proteins such as apolipoprotein A-IV, complement C3 and lipids such as PE (37:5), PE (O-38:5), PE (P-38:4), PC(40:7), PC(39:0), and PC(O-40:0) were identified on the MetS BC suggesting disease progression modifications. Proteins such as pulmonary surfactant protein A, fibrinogen alpha-chain and lipids such as CE (19:0)-NH4, DG (36:7), and DG (35:0)_C18:0 were increasingly present in the healthy BC over time, suggesting age-related interactions.DiscussionOverall, unique BCs were identified demonstrating the impact of age and disease progression on BC formation which will aid in understanding initial pulmonary NP-biomolecular interactions potentially contributing to susceptibility.

ObjectiveThe study aimed to explore the inhibitory effect of stevioside on colorectal cancer and its molecular mechanism.MethodsColorectal cancer cells were selected for functional testing, including the following groups: 0 μM stevioside, 1 μM stevioside, 2.5 μM stevioside and 5 μM stevioside. CCK-8 kit and EdU staining were employed to assess the cell viability. Cell apoptosis was deterred by flow cytometry. Western blot assay was utilized to detect the protein expressions of cleaved-caspase-3, Bax, Bcl-2, E-cadherin and Vimentin. The polarization of macrophage was evaluated through flow cytometry, western blot and immunofluorescence staining. The effect of stevioside on the proliferation of tumor tissue was detected by tumor formation and immunohistochemical staining in nude mice.ResultsStevioside exhibited a significant concentration-dependent inhibitory effect on the proliferation, migration, and invasion of colorectal cancer cells, while promoting apoptosis in vitro. Following stevioside treatment, there was a notable reduction in tumor volume and weight observed. Flow cytometry and immunohistochemical staining results showed that compared with control group, CD86+ cell ratio was increased in stevioside treatment group, while the CD206+ cell ratio was decreased in stevioside treatment group. RT-qPCR analysis revealed that, compared to the control group, stevioside treatment significantly reduced the mRNA expressions of Arg-1 and IL-10, while concomitantly increasing the mRNA expressions of IL-12 and TNF-α in a concentration-dependent manner.ConclusionStevioside possesses the ability to significantly hinder the proliferation of colorectal cancer cells and induce apoptosis, the mechanism of which may be closely related to the regulation of macrophage M1 polarization.

BackgroundHepatocellular carcinoma (LIHC), a prevalent liver cancer with a grim prognosis due to high recurrence rates, is under scrutiny for its association with zinc finger proteins (ZNFs) in tumorigenesis. This study aims to create a prognostic model for LIHC incorporating ZNF-related genes.MethodsBy analyzing TCGA data, we identified differentially expressed genes (DEGs) between normal and LIHC samples, focusing on ZNF-related genes through univariate Cox and LASSO Cox regression. A multivariate Cox regression model was built, categorizing LIHC patients into high- and low-ZNFRS groups based on ZNF-related risk scores. Model performance was evaluated using ROC curves, with a nomogram integrating clinical data and ZNFRS. Immune microenvironment, enrichment analysis, mutations, and drug responses in LIHC were also explored.ResultsA prognostic model utilizing 10 ZNF-related genes accurately predicted LIHC survival. The low-risk group exhibited enhanced immune cell infiltration, contrasting with cell cycle and DNA replication enrichment in the high-risk group, which also displayed increased mutation rates. Promising drug candidates like SNS-314 and Decitabine warrant further investigation in LIHC treatment.ConclusionThis study introduces impactful prognostic markers for LIHC management, emphasizing the significance of ZNFs in predicting patient outcomes and guiding treatment strategies.

ObjectiveTo explore the mechanisms by which microplastic toxicity leads to DNA damage in mouse spermatocytes.MethodsWe randomly divided GC-2 cells into a control group and a polystyrene microplastic (PS) group and then evaluated the DNA fragmentation index (DFI) in these cells via a comet assay. Whole-transcriptome sequencing was performed on the basis of DFI results. GO and KEGG enrichment analyses were based on the results of the entire transcriptome sequencing. At the same time, we also performed q-PCR validation on some significantly expressed genes and drew a toxicological network diagram on PS and mouse spermatocytes.ResultsComet assay results revealed that the intake of PS increased the DFI of mouse spermatocytes. Whole-transcriptome sequencing revealed that 61 circRNAs, 132 lncRNAs, 40 miRNAs, and 140 mRNAs were differentially expressed between the control and PS groups. GO and KEGG analyses revealed some notable enrichment in cellular components, molecular functions, biological processes, and gene expression pathways such as the defense response to viruses, the defense response to symbionts, the RIG-I-like receptor, the NOD-like receptor, and the calcium signaling pathways. Q-PCR and the network analysis revealed that PS affects the DFI of mouse spermatocytes mainly by influencing immune responses.ConclusionPS may damage the sperm DNA and increase the DFI by affecting cellular immunity-related pathways and redox pathways such as the RIG-I-like receptor and NOD-like receptor signaling pathways.

IntroductionBisphosphonates and denosumab are the most common antiresorptive drugs (ARs). ARs may cause medication-related osteonecrosis of the jaw (MRONJ) as a side effect, characterized by osteonecrosis and ulceration of the oral mucosa. The pathophysiology of MRONJ remains partly unclear and there is currently no consensus on its multietiological background. Immunomodulatory medications such as corticosteroids and antiestrogens may affect MRONJ onset.MethodsAn in vitro 3D cell culture model of gingival, keratinocytes, and fibroblasts were used to elucidate the pathogenesis of MRONJ. Cell cultures were exposed to ARs, followed by exposures to corticosteroids or antiestrogens. Morphology and proliferation were evaluated.ResultsAmong the ARs, alendronate caused the most negative cellular changes, while zoledronate only had a few effects. Denosumab caused more morphological cell atypia and proliferation than other ARs. The combined exposures of individual ARs with corticosteroids had some additional negative effects on gingival cells, whereas ARs with antiestrogen had few effects. The results are partly inconsistent, indicating that 3D cell culture experiments may not be the most suitable method for studying the effects of ARs.ConclusionThis study suggests that alendronate and denosumab affect gingival cell growth in a 3D cell culture model. These effects are smaller than reported in previous monolayer studies.

BackgroundAccurate and prompt assessment of malathion intoxication severity remains a significant clinical challenge, often hampered by reliance on single diagnostic markers. This exploratory case series investigated the combined utility of rapid butyrylcholinesterase (BChE) activity measurements and gas chromatography-tandem mass spectrometry (GC-MS/MS) for quantifying urinary malathion to enhance diagnostic precision.MethodsWe investigated three independent patients admitted with acute malathion intoxication. BChE activity was measured using both a point-of-care (POCT) device and a laboratory-based enzyme-multiplied immunoassay technique (EMIT). Urinary malathion was quantified using a validated GC-MS/MS method.ResultsMalathion exposure was confirmed in all patients via urinary analysis. Strong per-case positive correlations (r ranging from 0.905 to 0.996) were observed between the two BChE measurement methods, though Bland-Altman analysis revealed noteworthy discrepancies (mean bias of 10%, limits of agreement ranging from -20% to 40%). Critically, statistically significant inverse correlations (p < 0.05) were identified between urinary malathion concentrations and both BChE activity measurements, underscoring the dynamic relationship between exposure and enzymatic inhibition.ConclusionThese findings, derived from a small, exploratory case series, suggest the importance of an integrated diagnostic approach for malathion intoxication. This combined strategy may support improved assessment of severity and prognosis in individual cases, offering insights into the pesticide's systemic impact and elimination kinetics, especially when exposure details are unclear. While rapid BChE tests are valuable for initial screening, their interpretation should occur within this multi-marker framework. The generalizability of these findings is limited by the small sample size, and no formal power calculation was performed.