Human & experimental toxicology最新文献

IntroductionThis study aimed to investigate the mechanisms underlying Tripterygium glycosides (TG) - induced liver injury, focusing on the role of the STING-TBK1 signaling pathway, and to evaluate the therapeutic potential of inhibiting this axis in mitigating liver damage.MethodsThe study employed two experimental approaches. First, male Balb/c mice were administered TG at doses of 13.5, 40.5, and 135 mg/kg for 3 weeks to assess dose-dependent hepatotoxicity. Liver injury was evaluated through serum ALT/AST levels, hepatic histopathology, and liver index. Immunohistochemical staining and Western blot analysis were used to examine STING expression in liver tissues and THP-1 cells. In the second approach, pharmacological inhibitors of STING and TBK1 were administered to evaluate their protective effects against TG-induced liver injury.ResultsTG induced dose-dependent liver injury and inflammatory infiltration, along with activation of the STING-TBK1 pathway in non-parenchymal cells. Inhibition of this pathway significantly attenuated hepatotoxicity, as evidenced by reduced ALT/AST levels, decreased inflammatory cytokines, and improved histopathological outcomes.DiscussionThese findings demonstrate that the STING-TBK1 axis plays a critical role in mediating TG-induced hepatotoxicity. Pharmacological inhibition of this pathway effectively alleviates TG-induced hepatotoxicity, suggesting its potential as a therapeutic target for drug-induced liver injury.

IntroductionDiosbulbin B (DB) has emerged as a potential drug for tumor treatment, but its hepatotoxicity restricts clinical use. The role of autophagy in DB-induced liver damage remains unclear. This study investigates autophagy mechanisms in DB hepatotoxicity and the protective effect of Rosa roxburghii Tratt juice (RRTJ).MethodsRats were randomized into control group, DB (12.5, 25, 50 mg/kg), RRTJ control, and RRTJ + DB (5/10 mL/kg + 50 mg/kg), and orally administered for 1 month. Hepatic superoxide dismutase (SOD)/glutathione peroxidase (GSH-Px) activities, malondialdehyde (MDA) content, serum liver function markers, and liver histopathology were assessed. Gene and protein expression levels of Beclin1, LC3B, and p62 were detected by real-time quantitative polymerase chain reaction (qPCR), immunohistochemistry, and Western blot. QPCR and immunohistochemistry evaluated the potential role of AMPK.Results25 and 50 mg/kg DB induced liver damage by reducing the levels of SOD/GSH-Px in liver tissues and increasing MDA. Resulting in elevated serum AST levels and histopathological changes such as cytoplasmic loosening, punctate necrosis in hepatocytes. DB-induced liver injury was associated with autophagic dysfunction. Compared with the control group, DB-treated rats showed upregulated expression of autophagy-related proteins Beclin1, LC3B, and p62. RRTJ inhibited DB-induced AMPK phosphorylation and reduced the expression of Beclin1, LC3B, and p62, thereby attenuating liver injury.ConclusionDB induces liver injury via autophagy dysregulation, while RRTJ alleviates damage by reducing AMPK phosphorylation to modulate autophagy, suggesting RRTJ as a potential strategy against DB-induced hepatotoxicity.

IntroductionGlyphosate (GLP) is one of the most widely used herbicides in the world. However, its underlying effects on the liver remain unclear. This study aims to investigate the toxic effects and the gut microbiome- and serum metabolite-related mechanisms of GLP on the liver in mice.Methods16S rDNA sequencing and UPLC-Q-TOF-MS/MS were used to investigate the mechanisms of GLP toxicity in mice administered with 0, 50, 250 and 500 mg/kg/day GLP for 30 days.ResultsGLP induced hepatocyte edema and ballooning as well as inflammatory cell infiltration. Exposure to GLP resulted in increased levels of serum ALT, TBIL, DBIL, and GLU. Microbiota analysis at the phylum level demonstrated that the proportions of Patescibacteria decreased in the GLP-treated group. The genus-level analysis identified 11 different genera, with eight decreased and three increased in the GLP-exposed group. Metabolomics analysis of serum showed 42 differential metabolites between the GLP and control groups. The metabolic pathway enrichment analysis revealed that the pentose phosphate pathway (PPP) and pyrimidine metabolism were significantly activated. Spearman analysis showed that the changes in the differential metabolites of the PPP and pyrimidine metabolism and gut microbiota were strongly associated with the biochemical index.DiscussionIn conclusion, GLP exposure induces hepatic injury through alterations in the gut microbiome and metabolic pathways, particularly by activating the pentose phosphate pathway and pyrimidine metabolism.

IntroductionAdipose-derived mesenchymal stem cells (ADSCs) are promising candidates for regenerative therapies, but their clinical application is limited by cellular aging. This study investigated the effects of hydrogen on ADSC senescence and myogenic differentiation, along with the underlying molecular mechanisms.MethodsADSCs were treated with hydrogen gas. Senescence was assessed using β-galactosidase staining, proliferation assays, measurements of mitochondrial oxidative stress, and protein expression analysis. Differentiation capacity was evaluated through MyHC immunofluorescence, MYOD expression profiling, and quantification of myogenic regulatory factors. Additionally, the key molecular pathway of hydrogen's action was investigated by pharmacologically inhibiting PRDX6.ResultsThe findings showed that hydrogen treatment reduced senescence and increased differentiation capacity, as evidenced by higher proportions of MyHC-positive cells, increased myogenin levels, and decreased Muscle RING finger protein1 (MuRF1) expression. Molecular investigations revealed activation of the PRDX6/SIRT1/PGC-1α axis, accompanied by elevated NQO-1 expression. Importantly, pharmacological inhibition of PRDX6 largely eliminated the protective effects of hydrogen on cellular aging, disrupted differentiation, and caused mitochondrial dysfunction.DiscussionThese results suggest that hydrogen can regulate ADSC behavior via PRDX6-driven activation of SIRT1/PGC-1α signaling, offering potential approaches to improve stem cell quality for regenerative medicine.

BackgroundPraseodymium (Pr), Samarium (Sm), Lanthanum (La), and Terbium (Tb) are rare earth elements (REEs) that can accumulate in the body and induce oxidative stress (OS), which may contribute to polycystic ovary syndrome (PCOS), a condition affecting 116 million women worldwide. With the increasing use of REEs, understanding their role in PCOS is crucial.DesignThis case-control study included 56 PCOS cases and 50 healthy controls, with confounding factors such as age, BMI, and hormones controlled. Inductively Coupled Plasma Mass Spectrometry (ICP-MS) was used to measure serum levels of Pr, Sm, La, and Tb, and Pearson correlation was performed to explore their relationship with oxidative stress markers such as malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD).ResultA significant increase in serum levels of Pr, Sm, La, and Tb was observed in PCOS cases compared to controls (p < 0.05). The 95% confidence intervals (CIs) for the differences in serum Pr, Sm, La, and Tb levels were [0.0008, 0.0032], [0.0002, 0.0091], [0.0019, 0.0073], and [0.0002, 0.0129], respectively. Additionally, serum levels of MDA were significantly elevated, accompanied by reduction in the antioxidant markers-GSH and SOD (p < 0.001). Elevated REE levels were positively correlated with increased MDA and negatively correlated with GSH and SOD, indicating increased oxidative stress.ConclusionThese findings suggest that oxidative stress-induced metal intoxication may play a critical role in the development of PCOS. Future studies should explore the clinical significance of REE exposure and its potential as a target for preventive strategies in PCOS management.

IntroductionHigh-dose Vitamin C has shown significant anti-tumor effects in various cancers, including hematological malignancies. However, its therapeutic efficacy against acute lymphoblastic leukemia (ALL) remains underexplored.MethodsALL cell lines and normal bone marrow mononuclear cells were treated with Vitamin C to assess cell viability, apoptosis, proliferation, and cell cycle progression. Colony formation assays evaluated long-term growth. Additionally, transgenic mouse models were employed to evaluate the in vivo antitumor activity of high-dose Vitamin C in ALL. Western blotting, ROS detection 2',7'-Dichlorofluorescin diacetate (DCFH-DA), and RNA sequencing with GSEA were conducted to explore Vitamin C's mechanism of action.ResultsOur results demonstrated that high-dose Vitamin C exhibited potent cytotoxicity toward ALL cells at relatively low concentrations (200 μM) while sparing normal human bone marrow mononuclear cells even at concentrations as high as 1 mM. Vitamin C effectively inhibited ALL cell line proliferation, induced apoptosis, and disrupted cell cycle progression. We further identified that the increased expression of Solute Carrier Family 23 Member 1 (SLC23A1) in ALL cells enhanced their sensitivity to Vitamin C. In SLC23A1 knockout cells, treatment with 200 μM Vitamin C significantly restored cell viability and reduced apoptosis compared to controls. Mechanistically, high-dose Vitamin C induced apoptosis in ALL cells by activating the ER stress response through the PERK/CHOP pathway.ConclusionTaken together, our findings suggest that high-dose Vitamin C demonstrated significant anti-leukemic effects in ALL, showing cytotoxicity at 200 μM. Furthermore, SLC23A1 may serve as a potential biomarker for predicting the therapeutic response to Vitamin C treatment in ALL patients.